Thio-oxindole derivatives

ABSTRACT

This invention relates to compounds which are agonists of the progesterone receptor which have the general structure: 
                         
wherein:
     R 1 , R 2 , R 3 , R 4 , R 5  and Q 1  are as defined herein, or a pharmaceutically acceptable salt thereof, as well as methods of using these compounds to induce contraception or treat progesterone-related carcinomas and adenocarcinomas.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.10/420,276, filed Apr. 22, 2003, now U.S. Pat. No. 6,841,568 which is adivisional of U.S. patent application Ser. No. 10/253,380, filed Sep.24, 2002, now U.S. Pat. No. 6,583,145, issued Jun. 24, 2003, which is adivisional of U.S. patent application Ser. No. 10/022,467, filed Oct.30, 2001, now U.S. Pat. No. 6,521,657, which is a divisional of U.S.patent application Ser. No. 09/552,033, filed Apr. 19, 2000, now U.S.Pat. No. 6,355,648, which claims the benefit of the priority of U.S.Provisional Patent Application No. 60/172,259, filed May 4, 1999, nowabandoned.

BACKGROUND OF THE INVENTION

This invention relates to compounds which are agonists of theprogesterone receptor, their preparation and utility.

Intracellular receptors (IR) form a class of structurally related generegulators known as “ligand dependent transcription factors” (R. M.Evans, Science, 240, 889, 1988). The steroid receptor family is a subsetof the IR family, including progesterone receptor (PR), estrogenreceptor (ER), androgen receptor (AR), glucocorticoid receptor (GR), andmineralocorticoid receptor (MR).

The natural hormone, or ligand, for the PR is the steroid progesterone,but synthetic compounds, such as medroxyprogesterone acetate orlevonorgestrel, have been made which also serve as ligands. Once aligand is present in the fluid surrounding a cell, it passes through themembrane via passive diffusion, and binds to the IR to create areceptor/ligand complex. This complex binds to specific gene promoterspresent in the cell's DNA. Once bound to the DNA the complex modulatesthe production of mRNA and protein encoded by that gene.

A compound that binds to an IR and mimics the action of the naturalhormone is termed an agonist, whilst a compound which inhibits theeffect of the hormone is an antagonist.

PR agonists (natural and synthetic) are known to play an important rolein the health of women. PR agonists are used in birth controlformulations, typically in the presence of an ER agonist, alternativelythey may be used in conjunction with a PR antagonist. ER agonists areused to treat the symptoms of menopause, but have been associated with aproliferative effect on the uterus which can lead to an increased riskof uterine cancers. Co-administration of a PR agonist reduces/ablatesthat risk.

Jones, et al, described in U.S. Pat. No. 5,688,810 the PR antagonistdihydroquinoline A.

Jones, et al, described the enol ether B (U.S. Pat. No. 5,693,646) as aPR ligand.

Jones, et al, described compound C (U.S. Pat. No. 5,696,127) as a PRligand.

Zhi, et al, described lactones D, E and F as PR antagonists (J. Med.Chem., 41, 291, 1998).

Zhi, et al, described the ether G as a PR antagonist (J. Med. Chem., 41,291, 1998).

Combs, et al., disclosed the amide H as a ligand for the PR (J. Med.Chem., 38, 4880, 1995).

Perlman, et. al., described the vitamin D analog I as a PR ligand (Tet.Letters, 35, 2295, 1994).

Hamann, et al, described the PR antagonist J (Ann. N.Y. Acad. Sci., 761,383, 1995).

Chen, et al, described the PR antagonist K (Chen, et al, POI-37, 16^(th)Int. Cong. Het. Chem., Montana, 1997).

Kurihari, et. al., described the PR ligand L (J. Antibiotics, 50, 360,1997).

Kuhla, et al, taught the oxindole M as a cardiotonic (WO 86/03749).

Weber, described the oxindole N for cardiovascular indications (WO91/06545).

Fischer, et al, claim a preparation for making compounds which includethe generic structure O (U.S. Pat. No. 5,453,516).

R=variousSingh, et al, described the PDE III inhibitor P (J. Med. Chem., 37, 248,1994).

Andreani, et al, described the cytotoxic agent Q (Acta. Pharm. Nord., 2,407, 1990).

Binder, et al, described structure R which is an intermediate forpreparing COX II inhibitors (WO 97/13767).

Walsh (A. H. Robins) described the oxindole S as an intermediate (U.S.Pat. Nos. 4,440,785, 4,670,566).

Bohm, et al, claim the oxindole T as cardiovascular agents (WO91/06545).

Bohm, et al, include the generic structure U (WO 91/04974).

JP 63112584 A contains the generic structure V:

Boar, et al, described the dioxolane W as an intermediate forpreparation of acetylcholinesterase inhibitors (WO 93/12085 A1).

Kende, et al, described methodology for preparing 3,3-substitutedoxindoles, e.g. X, that was utilized in the present invention (Synth.Commun., 12, 1, 1982).

DESCRIPTION OF THE INVENTION

This invention provides compounds of the formulae 1 or 2:

wherein:

R₁ and R₂ are chosen independently from the group of H, alkyl,substituted alkyl; OH; O(alkyl); O(substituted alkyl); OAc; aryl;optionally substituted aryl; heteroaryl; optionally substitutedheteroaryl; alkylaryl; alkylheteroaryl; 1-propynyl; or 3-propynyl:

or R₁ and R₂ are joined to form a ring comprising one of the following:—CH₂(CH₂)_(n)CH₂—; —CH₂CH₂CMe₂CH₂CH₂—; —O(CH₂)_(m)CH₂—; O(CH₂)_(p)O—;—CH₂CH₂OCH₂CH₂—; or —CH₂CH₂N(H or alkyl)CH₂CH₂—;

m is an integer from 1 to 4;

n is an integer from 1 to 5;

p is an integer from 1 to 4;

or R₁ and R₂ together comprise a double bond to one of the following:CMe₂; C(cycloalkyl), O, C(cyloether).

R₃ is selected from H, OH, NH₂, C₁ to C₆ alkyl, substituted C₁ to C₆alkyl, C₃ to C₆ alkenyl, alkynyl or substituted alkynyl, or COR^(A);

R^(A) is selected from H, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, C₁to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl, orsubstituted C₁ to C₃ aminoalkyl;

R₄ is selected from H, halogen, CN, NH₂, C₁ to C₆ alkyl, substituted C₁to C₆ alkyl, C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, C₁ to C₆aminoalkyl, or substituted C₁ to C₆ aminoalkyl;

R₅ is selected from the groups a), b) or c):

-   -   a) R₅ is a trisubstituted benzene ring containing the        substituents X, Y and Z as shown below:

-   -   -   X is selected from halogen, OH, CN, C₁ to C₃ alkyl,            substituted C₁ to C₃ alkyl, C₁ to C₃ alkoxy, substituted C₁            to C₃ alkoxy, C₁ to C₃ thioalkyl, substituted C₁ to C₃            thioalkyl, S(O)alkyl, S(O)₂alkyl, C₁ to C₃ aminoalkyl,            substituted C₁ to C₃ aminoalkyl, NO₂, C₁ to C₃            perfluoroalkyl, 5 or 6 membered heterocyclic ring containing            1 to 3 heteroatoms, CONH₂, CSNH₂, CONHalkyl, CSNHalkyl,            CON(alkyl)₂, CSN(alkyl)₂, COR^(B), OCOR^(B), NR^(C)COR^(B);            -   R^(B) is selected from H, C₁ to C₃ alkyl, substituted C₁                to C₃ alkyl, aryl, substituted aryl, C₁ to C₃ alkoxy,                substituted C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl, or                substituted C₁ to C₃ aminoalkyl;            -   R^(C) is H, C₁ to C₃ alkyl, or substituted C₁ to C₃                alkyl;        -   Y and Z are independently selected from H, halogen, CN, NO₂,            C₁ to C₃ alkoxy, C₁ to C₃ alkyl, or C₁ to C₃ thioalkyl; or

    -   b) R₅ is a five or six membered heterocyclic ring with 1, 2, or        3 heteroatoms selected from O, S, SO, SO₂ or NR⁶ and containing        one or two independent substituents from the group of H,        halogen, CN, NO₂ and C₁ to C₃ alkyl, C₁ to C₃ alkoxy, C₁ to C₃        aminoalkyl, CORD, or NR^(E)COR^(D);        -   R^(D) is H, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl,            aryl, substituted aryl, C₁ to C₃ alkoxy, substituted C₁ to            C₃ alkoxy, C₁ to C₃ aminoalkyl, or substituted C₁ to C₃            aminoalkyl;        -   R^(E) is H, C₁ to C₃ alkyl, or substituted C₁ to C₃ alkyl;        -   R is H, or C₁ to C₃ alkyl; or

    -   c) R₅ is an indol-4-yl, indol-7-yl or benzo-2-thiophene moiety,        the moiety being optionally substituted by from 1 to 3        substituents selected from halogen, lower alkyl, CN, NO₂, lower        alkoxy, or CF₃;

Q¹ is S, NR₇, CR₈R₉;

R₇ is selected from the group including CN, C₁ to C₆ alkyl, substitutedC₁ to C₆ alkyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl,aryl, substituted aryl, heterocyclic, substituted heterocyclic, acyl,substituted acyl, aroyl, substituted aroyl, SO₂CF₃, OR¹¹ or NR¹¹R¹²;

R₈ and R₉ are independent substituents selected from the group of H, C₁to C₆ alkyl, substituted C₁ to C₆ alkyl, C₃ to C₈ cycloalkyl,substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocyclic,substituted heterocyclic, NO₂, CN, or CO₂R₁₀,

R₁₀ is C₁ to C₃ alkyl; or

CR₈R₉ comprises a six membered ring as shown by the structure below:

Q² is selected from the moieties:

R¹¹, R¹² and R¹³ are independently selected from H, C₁ to C₆ alkyl,substituted C₁ to C₆ alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, acyl, substituted acyl, aroyl or substitutedaroyl or sulfonyl;

or a pharmaceutically acceptable salt thereof.

A preferred list of substituents represented by R¹¹, R¹² and R¹³ ingroups of the compounds described herein are H, C₁ to C₆ alkyl,substituted C₁ to C₆ alkyl, —C(O)—(C₁ to C₆ alkyl), —S(O)₂—(C₁ to C₆alkyl), phenyl or benzyl.

It will be understood that this invention includes all tautomeric formsof the compounds, chemical formulae and substituents described herein.

Two preferred sets of compounds of this invention is depicted bystructures 2 and 3, respectively:

each wherein R₅ is a disubstituted benzene ring containing thesubstituents X and Y as shown below:

X is selected from halogen, CN, CONH₂, CSNH₂, CONHalkyl, CSNHalkyl,CONalkyl₂, CSNalkyl₂, C₁ to C₃ alkoxy, C₁ to C₃ alkyl, NO₂, C₁ to C₃perfluoroalkyl, 5 membered heterocyclic ring containing 1 to 3heteroatoms, or C₁ to C₃ thioalkoxy;

Y is a substituent on the 4′ or 5′ position from the group including H,halogen, CN, NO₂, C₁ to C₃ alkoxy, C₁ to C₄ alkyl, or C₁ to C₃thioalkyl; or a pharmaceutically acceptable salt thereof.

Another preferred group of formula 2 are those wherein R₅ is a fivemembered ring with the structure shown below:

wherein:

U is O, S, or NR₆;

R₆ is H, or C₁ to C₃ alkyl, or C₁ to C₄ CO₂alkyl;

X′ is selected from halogen, CN, NO₂, CONH₂, CSNH₂, CONHalkyl,CSNHalkyl, CONalkyl₂, CSNalkyl₂, C₁ to C₃ alkyl, or C₁ to C₃ alkoxy;

Y′ is from the group of H, F or C₁ to C₄ alkyl;

or a pharmaceutically acceptable salt thereof.

A further preferred subgroup of the compounds above are those in whichR₅ is a thiophene or furan ring substituted by X′ and Y′, as describedabove.

A further preferred subgroup group of compounds of formulas 2 and 3 arethose wherein R₅ is a six membered ring with the structure:

wherein X¹ is N or CX²,

X² is halogen, CN, CONH₂, CSNH₂, CONHalkyl, CSNHalkyl, CONalkyl₂,CSNalkyl₂ or NO₂;

Q¹ is S, NR₇, CR₈R₉;

R₇ is from the group including CN, C₁ to C₆ alkyl, substituted C₁ to C₆alkyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl,substituted aryl, heterocyclic, substituted heterocyclic, or SO₂CF₃;

R₈ and R₉ are independent substituents from the group including H, C₁ toC₆ alkyl, substituted C₁ to C₆ alkyl, C₃ to C₈ cycloalkyl, substitutedC₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocyclic, substitutedheterocyclic, NO₂, CN CO₂R₁₀,

R₁₀ is C₁ to C₃ alkyl;

CR₈R₉ are within a six membered ring as shown by the structure below:

or pharmaceutically acceptable salt thereof.

Still another preferred group of these compounds includes those havingthe general formulae:

each wherein R₅ is a disubstituted benzene ring containing thesubstituents X and Y as shown below:

X is selected from halogen, CN, CONH₂, CSNH₂, CONHalkyl, CSNHalkyl,CONalkyl₂, CSNalkyl₂, C₁ to C₃ alkoxy, C₁ to C₃ alkyl, NO₂, C₁ to C₃perfluoroalkyl, 5 membered heterocyclic ring containing 1 to 3heteroatoms, or C₁ to C₃ thioalkoxy;

Y is a substituent on the 4′ or 5′ position from the group including H,halogen, CN, NO₂, C₁ to C₃ alkoxy, C₁ to C₄ alkyl, or C₁ to C₃thioalkyl;

or a pharmaceutically acceptable salt thereof.

A further preferred subgroup group of compounds of formulae:

are those wherein R₅ is a six membered ring with the structure:

wherein X¹ is N or CX²,

X² is halogen, CN, CONH₂, CSNH₂, CONHalkyl, CSNHalkyl, CONalkyl₂,CSNalkyl₂ or NO₂;

Q² is as defined above;

R₇ is from the group including CN, C₁ to C₆ alkyl, substituted C₁ to C₆alkyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl,substituted aryl, heterocyclic, substituted heterocyclic, or SO₂CF₃;

R₈ and R₉ are independent substituents from the group including H, C₁ toC₆ alkyl, substituted C₁ to C₆ alkyl, C₃ to C₈ cycloalkyl, substitutedC₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocyclic, substitutedheterocyclic, NO₂, CN CO₂R₁₀,

R₁₀ is C₁ to C₃ alkyl;

CR₈R₉ are within a six membered ring as shown by the structure below:

or pharmaceutically acceptable salt thereof.

A further preferred set of compounds of this invention is depicted bystructure 4,

Wherein R₁₄ is chosen from the group H, acyl, substituted acyl, aroyl,substituted aroyl, sulfonyl, substituted sulfonyl.

Wherein R₅ is a disubstituted benzene ring containing the substituents Xand Y as shown below:

X is selected from halogen, CN, CONH₂, CSNH₂, CONHalkyl, CSNHalkyl,CON(alkyl)₂, CSN(alkyl)₂, CNHNHOH, CNH₂NOH, C₁ to C₃ alkoxy, C₁ to C₃alkyl, NO₂, C₁ to C₃ perfluoroalkyl, 5 membered heterocyclic ringcontaining 1 to 3 heteroatoms, or C₁ to C₃ thioalkoxy;

Y is a substituent on the 4′ or 5′ position from the group including H,halogen, CN, NO₂, C₁ to C₃ alkoxy, C₁ to C₄ alkyl, or C₁ to C₃thioalkyl;

or a pharmaceutically acceptable salt thereof.

Another preferred group of formula 4 are those wherein R₅ is a fivemembered ring with the structure shown below:

wherein:

U is O, S, or NR₆;

R₆ is H, or C₁ to C₃ alkyl, or C₁ to C₄ CO₂alkyl;

X′ is selected from halogen, CN, NO₂, CONH₂, CNHNHOH, CNH₂NOH, CSNH₂,CONHalkyl, CSNHalkyl, CONalkyl₂, CSNalkyl₂, C₁ to C₃ alkyl, or C₁ to C₃alkoxy;

Y′ is from the group of H, F or C₁ to C₄ alkyl;

or a pharmaceutically acceptable salt thereof.

A further preferred subgroup of the compounds above are those in whichR₅ is a thiophene or furan ring substituted by X′ and Y′, as describedabove.

A further preferred subgroup group of compounds of formula 4 are thosewherein R₅ is a six membered ring with the structure:

wherein X¹ is N or CX²,

X² is halogen, CN, CONH₂, CSNH₂, CONHalkyl, CSNHalkyl, CONalkyl₂,CSNalkyl₂ or NO₂;

R₇ is from the group including CN, C₁ to C₆ alkyl, substituted C₁ to C₆alkyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl,substituted aryl, heterocyclic, substituted heterocyclic, or SO₂CF₃;

R₈ and R₉ are independent substituents from the group including H, C₁ toC₆ alkyl, substituted C₁ to C₆ alkyl, C₃ to C₈ cycloalkyl, substitutedC₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocyclic, substitutedheterocyclic, NO₂, CN CO₂R₁₀,

R₁₀ is C₁ to C₃ alkyl;

or pharmaceutically acceptable salt thereof.

A further preferred set of compounds of this invention is depicted bystructure 5,

Wherein R₅ is a disubstituted benzene ring containing the substituents Xand Y as shown below:

X is selected from halogen, CN, CONH₂, CSNH₂, CONHalkyl, CSNHalkyl,CONalkyl₂, CSNalkyl₂, CNHNOH, C₁ to C₃ alkoxy, C₁ to C₃ alkyl, NO₂, C₁to C₃ perfluoroalkyl, 5 membered heterocyclic ring containing 1 to 3heteroatoms, or C₁ to C₃ thioalkoxy;

Y is a substituent on the 4′ or 5′position from the group including H,halogen, CN, NO₂, C₁ to C₃ alkoxy, C₁ to C₄ alkyl, or C₁ to C₃thioalkyl;

or a pharmaceutically acceptable salt thereof.

Another preferred group of formula 5 are those wherein R₅ is a fivemembered ring with the structure shown below:

wherein:

U is O, S, or NR₆;

R₆ is H, or C₁ to C₃ alkyl, or C₁ to C₄ CO₂alkyl;

X′ is selected from halogen, CN, NO₂, CONH₂, CSNH₂, CONHalkyl,CSNHalkyl, CONalkyl₂, CSNalkyl₂, C₁ to C₃ alkyl, or C₁ to C₃ alkoxy;

Y′ is from the group of H, F or C₁ to C₄ alkyl;

or a pharmaceutically acceptable salt thereof.

A further preferred subgroup of the compounds above are those in whichR₅ is a thiophene or furan ring substituted by X′ and Y′, as describedabove.

A further preferred subgroup group of compounds of formula 5 are thosewherein R₅ is a six membered ring with the structure:

wherein X¹ is N or CX²,

X² is halogen, CN, CONH₂, CSNH₂, CONHalkyl, CSNHalkyl, CONalkyl₂,CSNalkyl₂ or NO₂;

R₇ is from the group including CN, C₁ to C₆ alkyl, substituted C₁ to C₆alkyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl,substituted aryl, heterocyclic, substituted heterocyclic, or SO₂CF₃;

R₈ and R₉ are independent substituents from the group including H, C₁ toC₆ alkyl, substituted C₁ to C₆ alkyl, C₃ to C₈ cycloalkyl, substitutedC₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocyclic, substitutedheterocyclic, NO₂, CN CO₂R₁₀,

R₁₀ is C₁ to C₃ alkyl;

or pharmaceutically acceptable salt thereof.

A further preferred set of compounds of this invention is depicted bystructure 6,

Wherein R₁₅ is selected from the group H, Me, CO₂R, acyl, substitutedacyl, aroyl, substituted aroyl, alkyl, substituted alkyl, CN.

Wherein R₅ is a disubstituted benzene ring containing the substituents Xand Y as shown below:

X is selected from halogen, CN, CONH₂, CSNH₂, CONHalkyl, CSNHalkyl,CONalkyl₂, CSNalkyl₂ CNHNOH, C₁ to C₃ alkoxy, C₁ to C₃ alkyl, NO₂, C₁ toC₃ perfluoroalkyl, 5 membered heterocyclic ring containing 1 to 3heteroatoms, or C₁ to C₃ thioalkoxy;

Y is a substituent on the 4′ or 5′ position from the group including H,halogen, CN, NO₂, C₁ to C₃ alkoxy, C₁ to C₄ alkyl, or C₁ to C₃thioalkyl;

or a pharmaceutically acceptable salt thereof.

Another preferred group of formula 6 are those wherein R₅ is a fivemembered ring with the structure shown below:

wherein:

U is O, S, or NR₆;

R₆ is H, or C₁ to C₃ alkyl, or C₁ to C₄ CO₂alkyl;

X′ is selected from halogen, CN, NO₂, CONH₂, CSNH₂, CONHalkyl,CSNHalkyl, CONalkyl₂, CSNalkyl₂, C₁ to C₃ alkyl, or C₁ to C₃ alkoxy;

Y′ is from the group of H, F or C₁ to C₄ alkyl;

or a pharmaceutically acceptable salt thereof.

A further preferred subgroup of the compounds above are those in whichR₅ is a thiophene or furan ring substituted by X′ and Y′, as describedabove.

A further preferred subgroup group of compounds of formula 6 are thosewherein R₅ is a six membered ring with the structure:

wherein X¹ is N or CX²,

X² is halogen, CN, CONH₂, CSNH₂, CONHalkyl, CSNHalkyl, CONalkyl₂,CSNalkyl₂ or NO₂;

R₇ is from the group including CN, C₁ to C₆ alkyl, substituted C₁ to C₆alkyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl,substituted aryl, heterocyclic, substituted heterocyclic, or SO₂CF₃;

R₈ and R₉ are independent substituents from the group including H, C₁ toC₆ alkyl, substituted C₁ to C₆ alkyl, C₃ to C₈ cycloalkyl, substitutedC₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocyclic, substitutedheterocyclic, NO₂, CN CO₂R₁₀,

R₁₀ is C₁ to C₃ alkyl;

or pharmaceutically acceptable salt thereof.

A further preferred set of compounds of this invention is depicted bystructure 7,

Wherein R₅ is a disubstituted benzene ring containing the substituents Xand Y as shown below:

X is selected from halogen, CN, CONH₂, CSNH₂, CONHalkyl, CSNHalkyl,CONalkyl₂, CSNalkyl₂, CNHNOH, C₁ to C₃ alkoxy, C₁ to C₃ alkyl, NO₂, C₁to C₃ perfluoroalkyl, 5 membered heterocyclic ring containing 1 to 3heteroatoms, or C₁ to C₃ thioalkoxy;

Y is a substituent on the 4′ or 5′ position from the group including H,halogen, CN, NO₂, C₁ to C₃ alkoxy, C₁ to C₄ alkyl, or C₁ to C₃thioalkyl;

or a pharmaceutically acceptable salt thereof.

Another preferred group of formula 7 are those wherein R₅ is a fivemembered ring with the structure shown below:

wherein:

U is O, S, or NR₆;

R₆ is H, or C₁ to C₃ alkyl, or C₁ to C₄ CO₂alkyl;

X′ is selected from halogen, CN, NO₂, CONH₂, CSNH₂, CONHalkyl,CSNHalkyl, CONalkyl₂, CSNalkyl₂, C₁ to C₃ alkyl, or C₁ to C₃ alkoxy;

Y′ is from the group of H, F or C₁ to C₄ alkyl;

or a pharmaceutically acceptable salt thereof.

A further preferred subgroup of the compounds above are those in whichR₅ is a thiophene or furan ring substituted by X′ and Y′, as describedabove.

A further preferred subgroup group of compounds of formula 7 are thosewherein R₅ is a six membered ring with the structure:

wherein X¹ is N or CX²,

X² is halogen, CN, CONH₂, CSNH₂, CONHalkyl, CSNHalkyl, CONalkyl₂,CSNalkyl₂ or NO₂;

R₇ is from the group including CN, C₁ to C₆ alkyl, substituted C₁ to C₆alkyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl,substituted aryl, heterocyclic, substituted heterocyclic, or SO₂CF₃;

R₈ and R₉ are independent substituents from the group including H, C₁ toC₆ alkyl, substituted C₁ to C₆ alkyl, C₃ to C₈ cycloalkyl, substitutedC₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocyclic, substitutedheterocyclic, NO₂, CN, or CO₂R₁₀,

R₁₀ is C₁ to C₃ alkyl;

or pharmaceutically acceptable salt thereof.

The compounds of this invention may contain an asymmetric carbon atomand some of the compounds of this invention may contain one or moreasymmetric centers and may thus give rise to optical isomers anddiastereomers. While shown without respect to stereochemistry in Formula1 and 2 the present invention includes such optical isomers anddiastereomers; as well as the racemic and resolved, enantiomericallypure R and S stereoisomers; as well as other mixtures of the R and Sstereoisomers and pharmaceutically acceptable salts thereof.

The term “alkyl” is used herein to refer to both straight- andbranched-chain saturated aliphatic hydrocarbon groups having 1 to 8carbon atoms, preferably 1 to 6 carbon atoms; “alkenyl” is intended toinclude both straight- and branched-chain alkyl group with 1 or 2carbon-carbon double bonds and containing 2 to 8 carbon atoms,preferably 2 to 6 carbon atoms; “alkynyl” group is intended to coverboth straight- and branched-chain alkyl group with at least 1 or 2carbon-carbon triple bonds and containing 2 to 8 carbon atoms,preferably 2 to 6 carbon atoms.

The term “acyl” refers to a carbonyl substituent, including bothstraight- and branched-chain saturated aliphatic hydrocarbon groupshaving 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms. The term“substituted acyl” refers to an acyl group as just described optionallysubstituted with from 1 to 6 groups chosen from the list halogen, CN,OH, and NO₂.

The term “aroyl” also refers to a carbonyl substituent carrying a phenylgroup or a heteroaromatic group. The heteroaromatic groups of thisinclude 2-, 3- or 4-pyridinyl, 2- and 3-furanyl, 2- or 3-thiophenyl, or2- or 4-pyrimidinal. The term “substituted aroyl” also refers to anaroyl group as just described optionally substituted with from 1 to 6groups chosen from the list halogen, CN, OH, and NO₂.

The terms “substituted alkyl”, “substituted alkenyl”, and “substitutedalkynyl” refer to alkyl, alkenyl, and alkynyl as just described havingone or more substituents from the group including halogen, CN, OH, NO₂,amino, aryl, heterocyclic, substituted aryl, substituted heterocyclic,alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy,alkylamino, arylthio. These substituents may be attached to any carbonof alkyl, alkenyl, or alkynyl group provided that the attachmentconstitutes a stable chemical moiety.

The term “aryl” is used herein to refer to an aromatic system which maybe a single ring or multiple aromatic rings fused or linked together assuch that at least one part of the fused or linked rings forms theconjugated aromatic system. The aryl groups include, but are not limitedto, phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, andphenanthryl.

The term “substituted aryl” refers to aryl as just defined having 1 to 4substituents from the group including halogen, CN, OH, NO₂, amino,alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substitutedalkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio.

The term “heterocyclic” is used herein to describe a stable 4- to7-membered monocyclic or a stable multicyclic heterocyclic ring which issaturated, partially unsaturated, or unsaturated, and which consists ofcarbon atoms and from one to four heteroatoms selected from the groupincluding N, O, and S atoms. The N and S atoms may be oxidized. Theheterocyclic ring also includes any multicyclic ring in which any ofabove defined heterocyclic rings is fused to an aryl ring. Theheterocyclic ring may be attached at any heteroatom or carbon atomprovided the resultant structure is chemically stable. Such heterocyclicgroups include, for example, tetrahydrofuran, piperidinyl, piperazinyl,2-oxopiperidinyl, azepinyl, pyrrolidinyl, imidazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl,indolyl, quinolinyl, thienyl, furyl, benzofuranyl, benzothienyl,thiamorpholinyl, thiamorpholinyl sulfoxide, and isoquinolinyl.

The term “substituted heterocyclic” is used herein to describe theheterocyclic group just defined having 1 to 4 substituents selected fromthe group which includes halogen, CN, OH, NO₂, amino, alkyl, substitutedalkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy,aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino,or arylthio.

The term “thioalkyl” is used herein to refer to the SR group, where R isalkyl or substituted alkyl, containing 1 to 8 carbon atoms, preferably 1to 6 carbon atoms. The term “alkoxy” is used herein to refer to the ORgroup, where R is alkyl or substituted alkyl, containing 1 to 8 carbonatoms, preferably 1 to 6 carbon atoms. The term “aryloxy” is used hereinto refer to the OR group, where R is aryl or substituted aryl, asdefined above. The term “alkylcarbonyl” is used herein to refer to theRCO group, where R is alkyl or substituted alkyl, containing 1 to 8carbon atoms, preferably 1 to 6 carbon atoms. The term “alkylcarboxy” isused herein to refer to the COOR group, where R is alkyl or substitutedalkyl, containing 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms.The term “aminoalkyl” refers to both secondary and tertiary amineswherein the alkyl or substituted alkyl groups, containing 1 to 8 carbonatoms, preferably 1 to 6 carbon atoms, which may be either the same ordifferent and the point of attachment is on the nitrogen atom. The term“halogen” refers to Cl, Br, F, or I.

The compounds of this invention may be prepared according to the methodsdescribed below.

According to scheme 1, commercially available oxindole 3 is treated witha strong organo-metallic base (e.g. butyl lithium, lithiumdiisopropylamide, potassium hexamethyldisilazide) in an inert solvent(e.g. THF, diethyl ether) under nitrogen at reduced temperature (ca.−20° C.) (Kende, et al, Synth. Commun., 12, 1, 1982) in the presence oflithium chloride or N,N,N′,N′-tetramethylethylene-diamine. The resultingdi-anion is then treated with excess electrophile such as an alkylhalide, preferably an iodide. If R₁ and R₂ are to be joined such as theproduct 4 contains a spirocycle at position 3, then the electrophileshould be bifunctional, i.e. a diiodide. Subsequent bromination of 4proceeds smoothly with bromine in acetic acid (an organic co-solventsuch as dichloromethane may be added as required) in the presence ofsodium acetate, to afford the aryl bromide 5. The bromide 5 is reactedwith a palladium salt (e.g. tetrakis(triphenylphoshine)palladium(0) orpalladium acetate), in a suitable solvent (e.g. THF, dimethoxyethane,acetone, ethanol or toluene) at room temperature under an inertatmosphere (argon, nitrogen). The mixture is then treated with an arylor heteroaryl boronic acid or boronic acid ester and a base (sodiumcarbonate, triethylamine, potassium phosphate) in water or fluoridesource (cesium fluoride) under anhydrous conditions. The requiredproduct 6 is then isolated and purified by standard means.

Reaction of the indoline-2-one derivative 6 with either Lawessen'sreagent or phosphorous pentasulfide in a suitable organic solvent(pyridine, THF, dioxane, dimethoxyethane, dichloromethane, benzene,toluene, xylene) at a temperature between room temperature and thereflux temperature of the solvent provides access to the thiocarbonylderivative 7. An additive such as sodium hydrogen carbonate may also beuseful.

If R₁ and R₂ are different then the intermediate 4 is prepared byreacting the dianion of 3 with one equivalent of the electrophile R₁—X(X=leaving group e.g. iodine). The resultant mono-alkylated compound maythen be isolated and re-subjected to the reaction conditions using R₂—X,or alternatively used in-situ for the second alkylation with R₂—X.Alternatively if the desired product 7 is to contain R₂=H, then theisolated mono-alkylated intermediate is taken though the subsequentsteps.

Other methodologies are also available for coupling the pendant aryl orheteroaryl group, Ar, to the oxindole platform, for example reaction ofcompound S with an aryl or heteroaryl stannane, aryl or heteroaryl zinc,or aryl or heteroaryl magnesium halide in the presence of a palladium ornickel catalyst (scheme 2). The required aryl or heteroaryl-metallicspecies described above are formed through standard techniques.

Other functionalities can also be installed into the 3-position of theindoline platform according to scheme 3. Oxidation of the unsubstitutedindoline 8, preferably under neutral or acidic conditions (e.g. seleniumdioxide in dry dioxane at reflux) affords the isatin 9. Compound 9 maybe further functionalized to provide a ketal 11 by treatment with analcohol and acid catalyst under dehydrating conditions. Alternativelyreaction of 9 with a second ketone under suitable conditions (piperidinein toluene at reflux; or TiCl₄/Zn in THF at reflux) affords alkylidenederivatives 11. Reaction of the isatin 9 with a grignard reagent ororganolithium affords tertiary alcohols 12 (R=H). These alcohols maythen be further functionalized by alkylation or acylation procedures.

Reaction of the indoline-2-one derivative 6 with either Lawessen'sreagent or phosphorous pentasulfide in a suitable organic solvent(pyridine, THF, dioxane, dimethoxyethane, dichloromethane, benzene,toluene, xylene) at a temperature between room temperature and thereflux temperature of the solvent provides access to the thiocarbonylderivative 7. An additive such as sodium hydrogen carbonate may also beuseful.

An alternative mode of preparation is to react compound 5 with eitherLawessen's reagent or phosphorous pentasulfide in a suitable organicsolvent (pyridine, THF, dioxane, dimethoxyethane, dichloromethane,benzene, toluene, xylene) at a temperature between room temperature andthe reflux temperature of the solvent, under an inert atmosphere(nitrogen or argon) providing access to the thiocarbonyl derivative 13.Then reaction of bromide 13 in an anhydrous solvent (e.g. THF, Et₂O)with a strong base (sodium hydride preferred, sodiumhexamethyldisilazide, potassium hydride) followed by reaction at reducedtemperature (−50 to −20° C.) with n-butyllithium andN,N,N′,N′-tetramethylethylenediamine followed after a suitable period oftime by a trialkylborate (trimethyl or triisopropylborate) gives afteracidic work-up the boronic acid 14 (scheme 4). Compound 14 may then bereacted under palladium catalyzed conditions(tetrakis(triphenylphosphine)palladium(0) or palladium acetate, base(NaHCO₃, Na₂CO₃, K₂CO₃, triethylamine, CsF) solvent (toluene/EtOH/water,THF/water, dimethoxyethane/water, anhydrous dimethoxyethane)) with anaryl or heteroaryl bromide, aryl or heteroaryl iodide, aryl orheteroaryl trifluoromethane sulfonate or aryl or heteroarylfluorosulfonate, to provide the desired compounds 7.

Alternatively reaction of compound 13 under palladium catalyzedconditions (tetrakis(triphenylphosphine)palladium(0) or palladiumacetate, base (NaHCO₃, Na₂CO₃, K₂CO₃, triethylamine, CsF) solvent(acetone/water, toluene/EtOH/water, THF/water, dimethoxyethane/water,anhydrous dimethoxyethane)) with an aryl or heteroaryl bromide, aryl orheteroaryl iodide, aryl or heteroaryl trifluoromethane sulfonate or arylor heteroaryl fluorosulfonate, to provide the desired compounds 7.

Treatment of the bromide 5 in an anhydrous solvent (e.g. THF, Et₂O) witha strong base (sodium hydride preferred, sodium hexamethyldisilazide,potassium hydride) followed by reaction at reduced temperature (−50 to−20° C.) with n-butyllithium and N,N,N′,N′-tetramethylethylenediaminefollowed after a suitable period of time by a trialkylborate (trimethylor triisopropylborate) gives after acidic work-up the boronic acid 15(scheme 5). Compound 15 may then be reacted under palladium catalyzedconditions (tetrakis(triphenylphosphine)palladium(0), base (NaHCO₃,Na₂CO₃, K₂CO₃, triethylamine, CsF) solvent (toluene/EtOH/water,THF/water, dimethoxyethane/water, anhydrous dimethoxyethane)) with anaryl or heteroaryl bromide, aryl or heteroaryl iodide, aryl orheteroaryl trifluoromethane sulfonate or aryl or heteroarylfluorosulfonate, to provide the desired compounds 6.

An alternative strategy would be to prepare an organo zinc or magnesiumreagent from compound 5 and react it in-situ with an aryl or heteroarylbromide, aryl or heteroaryl iodide, aryl or heteroaryl trifluoromethanesulfonate of aryl or heteroaryl fluorosulfonate, under palladiumcatalyzed conditions to afford compound 6. Such an organo zinc ormagnesium species could be prepared by treatment of the bromide 5 in ananhydrous solvent (e.g. THF, Et₂O) with a strong base (sodium hydridepreferred, sodium hexamethyldisilazide, potassium hydride) followed byreaction at reduced temperature (−50 to −20° C.) with n-butyllithium andN,N,N′,N′-tetramethylethylenediamine followed after a suitable period oftime by reaction with anhydrous zinc chloride or magnesium bromide.

Reaction of the indoline-2-one derivative 6 with either Lawesson'sreagent or phosphorous pentasulfide in a suitable organic solvent(pyridine, THF, dioxane, dimethoxyethane, dichloromethane, benzene,toluene, xylene) at a temperature between room temperature and thereflux temperature of the solvent, under an inert atmosphere (nitrogenor argon) provides access to the thiocarbonyl derivative 15. An additivesuch as sodium hydrogen carbonate may also be useful.

According to scheme 6 thioamide derivatives 7 may be converted intoenamine derivatives 16 (Wrobel, et al, J. Med. Chem., 1989, 2493).

Thus reaction of thioamide 7 (Pg=H, 2-(trimethylsilyl)-ethoxymethyl,benzyl, etc) with triethyloxonium tetrafluoroborate followed by reactionwith a nucleophile (nitromethane, cyanamide,trifluoromethanesulfonamide, Meldrum's acid, etc) followed by removal ofthe protecting group under appropriate conditions (e.g.tetrabutylammonium fluoride in THF forPg=2-(trimethylsilyl)-ethoxymethyl) then gives the enamine derivatives16. Appropriate solvents for the two steps are selected fromdichloromethane, THF, dioxane, 1,2-dichloroethane, and the reaction isconducted at a temperature from −78° C. to the boiling point of thesolvent under an inert atmosphere (nitrogen or argon).

According to Scheme 7, treatment of intermediate 7 with an alkylatingagent, e.g., methyl iodide, ethyl iodide, 2,4-dinitrofluoro benzene, or4-nitro fluorobenzene, in the presence of a suitable base (e.g. an aminebase such as pyridine, triethylamine or di-iso-propylethylamine orlithium, sodium, potassium or cesium carbonate) in a suitable organicsolvent (e.g. DMF, THF, DMSO, dioxane or acetonitrile) at a temperaturebetween −78° C. and the boiling point of the solvent, would then affordthioimino ethers 17. Subsequent reaction of intermediates 17 withhydroxylamine or an acid salt of hydroxylamine (e.g. the hydrochloride)in a suitable solvent (for example but not limited to pyridine methanol,ethanol, iso-propanol, DMF, THF or DMSO and optionally in the presenceof an additive such as a tertiary amine base or sodium or potassiumacetate) at a temperature between −78° C. and the boiling point of thesolvent would then afford the N-hydroxyamidines 18.

Similarly treatment of intermediates 17 with a carbon nucleophile suchas a malonate derivative (e.g., malononitrile, a cyano acetate ester, anitro acetate ester or a malonate) in the presence of a suitable base(e.g. an amine base such as pyridine, triethylamine ordi-iso-propylethylamine or lithium, sodium, potassium or cesiumcarbonate) or a Lewis acid (e.g. boron trifluoride etherate, a lead IIsalt, titanium tetrachloride, a magnesium II salt, or a silver salt) ina solvent compatible with the chosen base or Lewis acid (e.g. DMF, THF,DMSO, dioxane or acetonitrile, chloroform, benzene, toluene ordichloromethane) would then afford the adduct 19. If the group R₃ inadduct 19 is an ester of a carboxylic acid, then it may bedecarboxylated directly to give the enamine derivative 20 by treatmentwith, e.g. sodium iodide in DMSO at a temperature between roomtemperature and the boiling point of the solvent. Alternatively theester may be first hydrolysed to the carboxylic acid (by treatment withan aqueous base (e.g. lithium, sodium, or potassium hydroxide) in asuitable solvent (e.g. THF, dioxane acetonitrile, methanol or ethanol)),followed by decarboxylation in the presence of an acid (e.g.hydrochloric or sulfuric acid) in a suitable solvent (e.g. acetonitrile,THF, dioxane) to afford the derivatives 20. Alternatively the xanthateester of the carboxylic acid may be prepared by reaction with a basesuch as sodium or potassium hydride in THF, followed by treatment withcarbon disulfide. Subsequent reaction with tributyl tin hydride atelevated temperatures in a solvent such as benzene or toluene under aninert nitrogen or argon atmosphere in the presence of a radicalinitiator such as benzoyl peroxide or azo-bis-iso-butyronitrile wouldthen give the product 20.

An alternative strategy for synthesizing the product 18 is illustratedby Scheme 8. Thus the bromide 13 (the corresponding chloride, iodide ortriflate ester may also be employed) is treated with an alkylatingagent, eg methyl iodide, ethyl iodide, 2,4-dinitrofluoro benzene, or4-nitro fluorobenzene, in the presence of a suitable base (e.g. an aminebase such as pyridine, triethylamine or di-iso-propylethylamine orlithium, sodium, potassium or cesium carbonate) in a suitable organicsolvent (e.g. DMF, THF, DMSO, dioxane or acetonitrile) at a temperaturebetween −78° C. and the boiling point of the solvent, would then affordthioimino ethers 21. Subsequent reaction of intermediate 21 withhydroxylamine or an acid salt of hydroxylamine (e.g. the hydrochloride,hydrobromide) in a suitable solvent (for example but not limited topyridine methanol, ethanol, iso-propanol, DMF, THF or DMSO andoptionally in the presence of an additive such as a tertiary amine baseor sodium or potassium acetate) at a temperature between −78° C. and theboiling point of the solvent, would then afford the N-hydroxyamidine 22.Intermediate 22 could then be protected with a compatible group (e.g.benzyl ether, acyl derivative, tetrahydropyranyl ether, methoxy methylether, silyl ether) to give the derivative 23. Alternately compound 21could be reacted directly with a protected hydroxylamine derivative(chosen, but not limited to the protecting groups described above) todirectly afford derivative 23. Compound 23 may then be reacted with apalladium salt (e.g. tetrakis(triphenylphoshine)palladium(0) orpalladium acetate), in a suitable solvent (e.g. THF, dimethoxyethane,acetone, ethanol or toluene) at room temperature under an inertatmosphere (argon, nitrogen). The mixture is then treated with an arylor heteroaryl boronic acid or boronic acid ester and a base (sodiumcarbonate, triethylamine, potassium phosphate) in water or fluoridesource (cesium fluoride) under anhydrous conditions, and the reactionmay then be heated to the boiling point of the solvent. The requiredproduct 24 is then isolated and purified by standard means.

Compound 24 may then be de-protected under the conditions prescribed bythe nature of the protecting group. For example if the protecting groupis a benzyl ether then treatment with boron tribromide or trimethylsilyliodide in a suitable solvent (dichloromethane for example) would affordthe compound 18. Other methods to remove the benzyl ether would involvehydrogenation (hydrogen gas or other hydrogen source such ascyclohexadiene or ammonium formate) in the presence of a palladiumcatalyst. Solvents suitable for such a process include methanol,ethanol, THF, ethyl acetate and dioxane, at a temperature between roomtemperature and the boiling point of the solvent. If the protectinggroup was an acetal derivative (tetrahydropyranyl or methoxymethylethers) then hydrolysis could be effected under acidic conditions(hydrochloric acid, sulfuric acid, p-toluene sulfonic acid or acidic ionexchange resin) in a solvent such as methanol, ethanol, THF dioxane oracetonitrile. If the protecting group was an acyl derivative (acetate,or benzoate for example) then hydrolysis could be effected under acidicconditions as described above or under basic conditions (lithium, sodiumor potassium hydroxide) in a solvent such as an alcohol, THF, dioxane oracetonitrile at a temperature between room temperature and the boilingpoint of the solvent. If the protecting group was a silyl ether thencompound 18 may be prepared by hydrolysing intermediate 24 under theacidic conditions described above or alternately by exposing compound 24to a fluoride source (eg potassium fluoride, cesium fluoride or tetrabutyl ammonium fluoride) in a solvent such as an alcohol, THF, dioxaneor acetonitrile at a temperature between room temperature and theboiling point of the solvent. An inert atmosphere of nitrogen or argonmay be necessary.

Another method of synthesizing compound 18 would be to convert theprotected N-hydroxy amidine 23 into a boronic acid or boronic acid ester(by lithium halogen exchange followed by quench with tri-isopropylborate, or palladium catalyzed coupling with diboron pinacolate) andthen couple this boronic acid or ester derivative with an aryl chloride,bromide, iodide or triflate under a suitable palladium catalysis systemas described previously. Subsequent deprotection as described for Scheme8 would afford the desired compounds 18.

According to Scheme 9, treatment of the N-hydroxyamidine 18 underreducing conditions (e.g. catalytic hydrogenation, iron in acetic acidor hydrazine-raney nickel) would then afford intermediate 25. Solventssuitable for such a process include methanol, ethanol, THF, ethylacetate and dioxane, at a temperature between room temperature and theboiling point of the solvent. Protection of the secondary nitrogen (atertiary butyl carbamate is shown as a non-limiting example) understandard conditions would then give compound 26. Reaction of compound 26with an electrophilic cyanating agent (e.g. cyanogen bromide,N-cyanobenzotriazole or cyanogen bromide/4-dimethylaminopyridinecomplex) in a suitable solvent (THF acetonitrile or DMF, optionally inthe presence of a base such as pyridine or sodium hydride or potassiumtert-butoxide) may then afford the desired compound 27. In some casesthe cyanation step may occur with concomitant removal of the secondarynitrogen protecting group, if this deprotection does not occur in-situthen a further hydrolysis step would be required.

An alternate synthesis of compound 27 may follow that of compound 18,Scheme 8, where an N-cyanoamidine bromide 28, prepared from compound 22adopting a similar strategy to the reactions shown in scheme 9, could becoupled with a suitable functionalised aryl boronic acid or boronic acidester to give compound 27. In another strategy intermediate 28 may beconverted into the corresponding boronic acid or boronic acid ester andcoupled in a Suzuki or Suzuki type palladium coupling with a suitablefunctionalised aryl bromide.

The compounds of the present invention can be used in the form of saltsderived from pharmaceutically or physiologically acceptable acids orbases. These salts include, but are not limited to, the following saltswith inorganic acids such as hydrochloric acid, sulfuric acid, nitricacid, phosphoric acid and, as the case may be, such organic acids asacetic acid, oxalic acid, succinic acid, and maleic acid. Other saltsinclude salts with alkali metals or alkaline earth metals, such assodium, potassium, calcium or magnesium in the form of esters,carbamates and other conventional “pro-drug” forms, which, whenadministered in such form, convert to the active moiety in vivo.

This invention includes pharmaceutical compositions and treatments whichcomprise administering to a mammal a pharmaceutically effective amountof one or more compounds as described above, or a pharmaceuticallyacceptable salt thereof, as agonists of the progesterone receptor.

The compounds of this invention have been shown to act as competitiveinhibitors of progesterone binding to the PR and act as agonists. Thesecompounds may be used for contraception and post menopausal hormonereplacement therapy.

The progesterone receptor agonists of this invention, used alone or incombination, can be utilized in methods of contraception and thetreatment and/or prevention of dysfunctional bleeding, uterineleiomyomata, endometriosis; polycystic ovary syndrome, carcinomas andadenocarcinomas of the endometrium, ovary, breast, colon, prostate.Additional uses of the invention include stimulation of food intake.

When the compounds are employed for the above utilities, they may becombined with one or more pharmaceutically acceptable carriers orexcipients, for example, solvents, diluents and the like, and may beadministered orally in such forms as tablets, capsules, dispersiblepowders, granules, or suspensions containing, for example, from about0.05 to 5% of suspending agent, syrups containing, for example, fromabout 10 to 50% of sugar, and elixirs containing, for example, fromabout 20 to 50% ethanol, and the like, or parenterally in the form ofsterile injectable solutions or suspensions containing from about 0.05to 5% suspending agent in an isotonic medium. Such pharmaceuticalpreparations may contain, for example, from about 25 to about 90% of theactive ingredient in combination with the carrier, more usually betweenabout 5% and 60% by weight.

The effective dosage of active ingredient employed may vary depending onthe particular compound employed, the mode of administration and theseverity of the condition being treated. However, in general,satisfactory results are obtained when the compounds of the inventionare administered at a daily dosage of from about 0.5 to about 500 mg/kgof animal body weight, preferably given in divided doses two to fourtimes a day, or in a sustained release form. For most large mammals, thetotal daily dosage is from about 1 to 100 mg, preferably from about 2 to80 mg. Dosage forms suitable for internal use comprise from about 0.5 to500 mg of the active compound in intimate admixture with a solid orliquid pharmaceutically acceptable carrier. This dosage regimen may beadjusted to provide the optimal therapeutic response. For example,several divided doses may be administered daily or the dose may beproportionally reduced as indicated by the exigencies of the therapeuticsituation.

These active compounds may be administered orally as well as byintravenous, intramuscular, or subcutaneous routes. Solid carriersinclude starch, lactose, dicalcium phosphate, microcrystallinecellulose, sucrose and kaolin, while liquid carriers include sterilewater, polyethylene glycols, non-ionic surfactants and edible oils suchas corn, peanut and sesame oils, as are appropriate to the nature of theactive ingredient and the particular form of administration desired.Adjuvents customarily employed in the preparation of pharmaceuticalcompositions may be advantageously included, such as flavoring agents,coloring agents, preserving agents, and antioxidants, for example,vitamin E, ascorbic acid, BHT and BHA.

The preferred pharmaceutical compositions from the standpoint of ease ofpreparation and administration are solid compositions, particularlytablets and hard-filled or liquid-filled capsules. Oral administrationof the compounds is preferred.

These active compounds may also be administered parenterally orintraperitoneally. Solutions or suspensions of these active compounds asa free base or pharmacologically acceptable salt can be prepared inwater suitably mixed with a surfactant such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid, polyethyleneglycols and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparations contain a preservative to preventthe growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringe ability exits. It must be stable underconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacterial and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol (e.g., glycerol, propylene glycol and liquid polyethyleneglycol), suitable mixtures thereof, and vegetable oil.

This invention is further understood by the following non-limitingexamples.

EXAMPLE 15′-(3-CHLOROPHENYL)SPIRO[CYCLOHEXANE-1,3′-[3H]INDOLE]-2′(1′H)-THIONE

Spiro[cyclohexane-1,3′-[3H]indol]-2′-(1′H)one

A solution of oxindole (25 g, 0.19 mol) in anhydrous tetrahydrofuran(800 cm³) was cooled to −20° C., then n-butyllithium (2.5M in hexanes,152 cm³, 0.38 mol) was added slowly followed byN,N,N′,N′-tetramethylethylenediamine (51 cm³, 0.38 mol,). After 15 min.1,5-diiodopentane (174 g, 0.54 mol) was added slowly and the mixture wasallowed to warm to room temperature. After stirring for 16 h. saturatedaqueous ammonium chloride solution (1 L) and EtOAc (1 L) were added.After 15 min., the layers were separated and the aqueous phase wasextracted with EtOAc (×2). The combined organic layers were extractedwith hydrochloric acid (1N), then washed with brine (500 cm³), dried(MgSO₄), and concentrated to obtain an oil. The oil was triturated withhexane (200 cm³) and benzene (20 cm³). The precipitate was collected anddried in vacuo to obtain the subtitled compound (26.3 g, 69.6%) ascolorless crystals: mp 110–114° C.; ¹H NMR (DMSO-d₆) δ 1.67 (m, 10H),6.84 (d, 1H, J=8 Hz), 6.94 (t, 1H, J=8 Hz), 7.17 (t, 1H, J=8 Hz), 7.44(d, 1H, J=8 Hz), 10.3 (s, 1H).

5′-Bromospiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one

To a solution of spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one (17.6 g,0.09 mol) in acetic acid (300 cm³) was added sodium acetate (8.0 g, 0.1mol) and bromine (14.6 g, 0.091 mol) with stirring. After 30 min. atroom temperature, the reaction mixture was partitioned between water andEtOAc. The aqueous phase was extracted twice with EtOAc. The combinedorganic layers were washed with water, dried (MgSO₄) and evaporated andthe residue was triturated with hexane. The precipitate was collected,and dried in vacuo to obtain the subtitled compound (16.5 g, 67%) asoff-white crystals: mp 196–199° C.; ¹H NMR (DMSO-d₆) δ 1.62 (m, 10H),6.8 (d, 1H, J=6.8 Hz), 7.36 (d, 1H, J=8.2, 1.8 Hz), 7.58 (dd, 1H, J=8.2,1.8 Hz), 10.44 (s, 1H).

5-(3-chlorophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one

A solution of 5′-bromospiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one(0.32 g, 1.14 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.14g, 0.12 mmol) in dimethoxyethane (6 cm³) was stirred under N₂ for 20min. To this mixture was then added 3-chlorophenylboronic acid (0.21 g,1.37 mmol) and sodium carbonate (0.36 g, 3.4 mmol) in water (3 cm³). Thesolution was brought to reflux for 6 h then cooled to RT, poured intowater and extracted with EtOAc (×3). The combined organic extracts werewashed with water, brine, dried (MgSO₄), and evaporated. The residue waspurified by column chromatography (SiO₂, ethyl acetate:hexane 1:3) toafford the subtitled compound (0.28 g, 0.89 mmol, 80%) as a yellowsolid: mp. 164–165° C., ¹H NMR (CDCl₃) δ 1.60–1.78 (m, 6H), 1.81–1.99(m, 4H), 7.04 (d, J=8.1 Hz, 1H), 7.22–7.47 (m, 4H), 7.53 (s, 1H), 7.61(s, 1H), 9.28 (br s, 1H); ¹³C-NMR (CDCl₃) 20.17, 24.12, 31.92 (t), 47.22(s), 109.21, 121.94, 124.06, 125.50, 125.79, 125.97, 126.38, 128.96 (d),132.88, 133.59, 135.60, 139.14, 142.17, 182.89 (s); MS (EI) m/z 310, 312(M−H)⁺; Anal. (C₁₉H₁₈ClNO) C, H, N.

To a solution of5′-(3-Chlorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one (0.63g, 2.0 mmol) in dry xylene (20 cm³) under nitrogen was added2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide(0.89 g, 2.2 mmol) and the mixture heated under reflux. After 72 h, themixture was evaporated and the residue subjected to columnchromatography (SiO₂, EtOAc:hexane, gradient elution) to afford a solidwhich was re-crystallized from di-iso-propylether/hexane to afford thetitle compound as yellow crystals (0.17 g, 0.51 mmol, 26%): mp. 223–227°C.; ¹H-NMR (CDCl₃) δ 1.53–1.66 (m, 8H), 1.83–2.05 (m, 4H), 2.07–2.17 (m,2H), 7.11 (d, 1H, J=8.0 Hz), 7.31–7.53 (m, 3H), 7.54 (s, 1H), 7.86 (s,1H), 9.93 (s, 1H, br): MS ((+)APCI) m/z 328 (M+H)⁺.

EXAMPLE 23-(1′,2′-DIHYDRO-2′-THIOXOSPIRO[CYCLOHEXANE-1,3′-[3H]INDOL]-5′-YL)BENZONITRILE

To a solution of 5′-bromospiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one(1.00 g, 3.57 mmol) in dimethoxyethane (20 cm³) was addedtetrakis(triphenylphosphine)palladium (0.20 g, 0.17 mmol). After 15 min.3-formylphenylboronic acid (1.00 g, 6.93 g) was added followed bypotassium carbonate (2.90 g, 21 mmol) in water (10 cm³). After 20 h atreflux, the mixture was cooled poured into water and extracted withEtOAc (×3). The combined organic extract was washed with saturatedbrine, dried (MgSO₄) and evaporated. The residue was purified by columnchromatography (SiO₂, EtOAc:hexane, gradient elution) to afford thetitle compound (0.66 g, 2.15 mmol, 60%) as a white solid, ¹H NMR (CDCl₃)δ 1.65–1.85 (m, 6H), 1.86–2.08 (m, 4H), 7.22 (d, 1H, J=8 Hz), 7.48 (dd,1H, J=8, 2 Hz), 7.61 (t, 1H, J=8 Hz), 7.66 (d, 1H, J=2 Hz), 7.81–7.88(m, 2H), 8.06 (t, 1H, J=2 Hz), 8.30 (s, 1H, br); MS ((+)ESI) m/z 306(M+H)⁺.

3-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)benzaldehydeoxime

To a solution of3-(1′,2′-dihydro-2′-oxospirocyclohexane-1,3′-[3H]indol-5′-yl)benzaldehyde(0.59 g, 1.95 mmol) in EtOH:H₂O (10 cm³, 8:2) was added hydroxylaminehydrochloride (0.17 g, 2.5 mmol) and sodium acetate (0.20 g, 2.5 mmol).After 20 min. the mixture was concentrated water was added and theproduct extracted with EtOAc (×2). The combined organic layers werewashed with sat. sodium hydrogen carbonate solution, water, sat. brine,dried (MgSO₄) and evaporated to afford the subtitled oxime (0.63 g, 1.95mmol, 100%) which was used without further purification, ¹H NMR (CDCl₃)δ 1.60–1.84 (m, 6H), 1.85–2.00 (m, 4H), 6.86 (d, 1H, J=8 Hz), 7.36 (dd,1H, J=8, 2 Hz), 7.43–7.50 (m, 1H), 7.57–7.67 (m, 2H), 7.85 (s, 1H, br),8.25 (s, 1H), 8.68 (s, 1H, br), 8.94 (s, 1H, br); MS ((−)ESI) m/z 319(M−H)⁻.

3-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)benzonitrile

A solution of3-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol-5′-yl)benzaldehydeoxime (0.48 g, 1.49 mmol) in chloroform (10 cm³) was treated withselenium dioxide (0.38 g, 3.50 mmol) and heated under reflux. After 16h, the mixture was concentrated and the residue purified by columnchromatography (SiO₂, EtOAc:hexane 1:4) and the product re-crystallizedfrom EtOAc-hexane to afford the subtitled compound (0.161 g, 0.53 mmol,35%) as a white solid: mp. 190–191° C.; ¹H NMR (CDCl₃) δ 1.59–1.87 (m,6H), 1.88–2.09 (m, 4H), 7.03 (d, 1H, J=8 Hz), 7.42 (dd, 1H, J=8, 2 Hz),7.54 (t, 1H, J=8 Hz), 7.58–7.65 (m, 2H), 7.78 (dt, 1H, J=7, 2 Hz), 7.83(m, 1H), 8.26 (s, 1H, br); MS ((+) ESI) m/z 303 (M+H)⁺.

Reaction of3-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)benzonitrileand Lawesson's reagent according to the procedure in example 1 gave thetitle compound: mp. >231° C. (decomp.); ¹H NMR (DMSO-d₆) δ 1.38–1.55 (m,3H), 1.82–1.99 (m, 7H), 7.16 (d, 1H, J=8.1 Hz), 7.63–7.69 (m, 2H), 7.80(d, 1H, J=7.7 Hz), 8.01 (d, 1H, J=8 Hz) and 12.76 (s, 1H); MS ((−)-APCI)m/z 317 [M−H]⁻.

EXAMPLE 34-(1′,2′-DIHYDRO-2′-THIOXOSPIRO[CYCLOHEXANE-1,3′-[3H]INDOL]-5′-YL)-2-THIOPHENECARBONITRILE

3-(Trimethylstannyl)-2-thiophenecarbonitrile

A solution of 3-bromo-2-thiophenecarbonitrile (0.8 g, 4.3 mmol),tetrakis(triphenylphosphine)palladium(0) (0.25 g, 0.2 mmol) andhexamethylditin (1.4 g, 4.3 mmol) in dimethoxyethane (5 cm³) was heatedunder reflux for 14 h then cooled to RT. The reaction mixture wasabsorbed onto florisil and purified by column chromatography (SiO₂,methylene chloride:hexane 1:9) to afford the subtitled compound (1.04 g,3.8 mmol, 90%) as a clear viscous oil: ¹H NMR (CDCl₃) δ 0.35 (s, 9H),7.56 (d, J=0.9 Hz, 1H), 7.66 (d, J=0.9 Hz, 1H).

4-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-2-thiophenecarbonitrile

A solution of the 5′-bromospiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one(0.53 g, 1.9 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.1 g,0.14 mmol) and triphenylarsine (0.14 g, 0.47 mmol) in dimethoxyethane (8cm³) was stirred under N₂ for 20 minutes. To this mixture was then added3-(trimethylstannyl)-2-thiophenecarbonitrile (0.64 g, 2.35 mmol). Thesolution was brought to reflux for 32 h. After cooling to roomtemperature the reaction mixture was absorbed onto florisil and purifiedby column chromatography (SiO₂, ethyl acetate:hexane 2:3) to afford thesubtitled compound (0.43 g, 1.39 mmol, 74%) as an off white solid: ¹HNMR (CDCl₃) δ 1.56–2.1 (m, 10H), 6.97 (d, J=8.0 Hz, 1H), 7.39 (dd,J=8.03, 1.45 Hz, 1H), 7.57 (d, J=1.45 Hz, 1H), 7.59 (d, J=1.4 Hz, 1H),7.84 (d, J=1.4 Hz, 1H), 8.32 (br s, 1H); ¹³C-NMR (CDCl₃) δ 22.07, 26.56,34.4 (t), 48.13 (s), 110.18 (d), 111.3, 114.75 (s), 122.92, 126.76 (d),128.44 (s), 137.55 (d), 138.11, 142.71, 144.49, 182.13 (s); MS (EI) m/z307 (M−H)⁺; Anal. (C₁₈H₁₆N₂OS) C, H, N.

A solution of4-(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-2-thiophenecarbonitrile(1.0 g, 3.2 mmol) and Lawesson's Reagent (1.3 g, 3.2 mmol) in o-xylene(20 mL) was heated for two and a half hours. The reaction mixture waswashed with distilled water (5×100 mL), dried over MgSO₄, andevaporated. The product was purified by column chromatography (SiO₂,EtOAc:Hexane 1:5) to afford the title compound (0.2 g, 20%) as apale-yellow solid: m.p. 230–232° C.; ¹H-NMR (DMSO-d₆) δ 12.72 (s, 1H),8.52 (d, 1H, J=1.5 Hz), 8.36 (d, 1H, J=1.5 Hz), 8.00 (d, 1H, J=1.5 Hz),7.69 (dd, 1H, J=6.4, 1.8 Hz), 7.10 (d, 1H, J=8.3 Hz), 1.98–1.77 (m, 7H),1.43–1.33 (m, 3H); MS (EI) M⁺ @ m/z 324.

EXAMPLE 43-(1,2-DIHYDRO-2-THIOXOSPIRO[CYCLOHEXANE-1,3-[3H]INDOL]-5-YL)-5-FLUOROBENZONITRILE

To a solution of 5′-bromospiro[cyclohexane-1,3′-[3H]indol]-2′-(1′H)-one(11 g, 0.04 mol) in dry tetrahydrofuran (200 cm³) was added sodiumhydride (60% dispersion in mineral oil, 1.6 g, 0.04 mol). After 30 min.stirring at room temperature, the mixture was cooled to −78° C. andbutyl lithium (1.7M in hexanes, 23.2 cm³, 0.04 mol) was added slowly.After 30 min. di-iso-propylborate (25 cm³, 0.11 mol) was added and themixture was allowed to warm to room temperature. After 2 hrs.hydrochloric acid (1N, 500 cm³) and ethylacetate (500 cm³) were added.The aqueous phase was extracted with ethylacetate, then the combinedorganic layers were washed with water, brine, dried (MgSO₄) andevaporated. The residue was triturated with hexane and the precipitatedried in vacuo to obtain(2′-oxo-2,3-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)boronic acid(8.3 g, 86%) as an off-white solid that was used without furtherpurification. A sample that was further triturated with ethyl acetatehad the following properties: mp. 255–260° C. dec.; ¹H NMR (DMSO-d₆) δ1.50 (m, 2H), 1.73 (m, 8H), 6.82 (d, 1H, J=7.72 Hz), 7.66 (d, 1H, J=7.72Hz), 7.91 (s, 3H, br), 10.36 (s, 1H); MS ((−)ESI) m/z 244 [M−H].

3-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-5-fluorobenzonitrile

To a solution of 3,5-dibromofluorobenzene in diethyl ether (100 cm³) at−78° C. was added n-butyl lithium (2.5 M, 8 cm³, 20 mmol) dropwise.After 30 min. the mixture was treated with DMF (20 cm³ diethyl ether (10cm³ stirring was continued at −78° C. After 30 min. the mixture wasquenched with dilute HCl aq., separated and the aqueous layer wasextracted with EtOAc. The combined organic layers were combined, washedwith water, brine, dried (MgSO₄) and evaporated to give3-fluoro-5-bromobenzaldehyde (4.0 g, 19.7 mmol, 100%) as an oil: ¹H NMR(CDCl₃) δ inter alia 7.50–7.53 (m, 2H), 7.82 (s, 1H) and 9.93 (m, 1H);MS (EI) m/z 202, 204 [M⁺].

To a solution of the last cited compound (4.0 g, 19.7 mmol) inethanol:water (8:2, 50 cm³), was added sodium acetate (1.72 g, 21 mmol)and hydroxylamine hydrochloride (1.45 g, 21 mmol), and the mixture washeated under reflux. After 30 min., the mixture was cooled, evaporatedand the residue partitioned between water and EtOAc. The aqueous layerwas re-extracted with EtOAc and the combined organic layers were washedwith water, saturated sodium hydrogen carbonate solution, brine, dried(MgSO₄) and evaporated to give 3-fluoro-5-bromobenzaldehyde oxime (3.76g, 17.24 mmol, 87%) which was used without further purification: ¹H NMR(CDCl₃) δ 7.24–7.27 (m, 2H), 7.50 (s, 1H), 7.68 (s, 1H) and 8.04 (s,1H); MS (EI) m/z 217 [M⁺].

The above oxime (3.76 g, 17.24 mmol) and copper (II) acetate (370 mg)were dissolved in acetonitrile (100 cm³) under nitrogen and heated underreflux. After 5 h, the mixture was evaporated, the residue taken intoEtOAc, washed with sulfuric acid (1N), water, brine, dried (MgSO₄) andevaporated to give 3-fluoro-5-bromobenzonitrile (3.08 g, 15.39 mmol,89%) which was used without further purification.

The above bromide (3.0 g, 15 mmol) andtetrakis(triphenylphosphine)palladium (0) (0.86 g, 0.75 mmol) weredissolved in dimethoxyethane (130 cm³) under nitrogen. After 15 min.(2′-oxo-2,3-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)boronic acid(2.82 g, 11.5 mmol) and sodium carbonate (3.1 g, 29.3 mmol) dissolved inwater (40 cm³) were added, and the mixture heated under reflux. After 8h the mixture was cooled, poured into water and extracted with EtOAc(×3). The combined organic layers were then washed with water, dried(MgSO₄) and evaporated. The residue was then purified by columnchromatography (EtOAc:hexane, gradient elution), and the productrecrystallized from methanol to give3-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-5-fluorobenzonitrile(1.78 g, 5.55 mmol, 48%): mp 199–205° C.; ¹H NMR (CDCl₃) δ 1.64–2.03 (m,10H), 7.03 (d, 1H, J=8 Hz), 7.31 (dt, 1H, J=7.7 and 1.6 Hz), 7.41 (dd,1H, J=8, 1.7 Hz), 7.49 (dt, 1H, J=9.6, 2 Hz), 7.58 (d, 1H, J=2 Hz), 7.64(s, 1H) and 8.37 (s, 1H): MS (EI) m/z 320 [M⁺].

To a solution of3-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-5-fluorobenzonitrile(0.32 g, 1.0 mmol) in xylenes (10 cm³) under nitrogen was addedLawesson's reagent (0.89 g, 2.22 mmol) and the reaction was heated underreflux. After 4 h., the mixture was cooled, evaporated and the residuesubjected to column chromatography (SiO₂, EtOAc:hexane, gradientelution) to afford (0.143 g, 0.42 mmol, 42%) as a white solid: mp.236–250° C.; ¹H NMR (CDCl₃) δ 1.54–1.66 (m, 3H), 1.86–2.18 (m, 7H), 7.16(d, 1H, J=8.1 Hz), 7.33–7.36 (m, 1H), 7.46–7.52 (m, 2H), 7.65 (s, 1H),7.85 (d, 1H, J=1 Hz), 10.05 (s, 1H); MS ((+)-APCI) m/z 337 [M+H]⁺.

EXAMPLE 54-METHYL-5-(1,2-DIHYDRO-2-THIOXOSPIRO[CYCLOHEXANE-1,3-[3H]-INDOL]-5-YL)-2-THIOPHENETHIOAMIDE

2′-oxo-2′,3′-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)boronic acid(2.45 g, 10 mmol), 2-bromo-5-cyano-3-methylthiophene (2.4 g, 12 mmol),potassium (4 g, 29 mmol), and tetrakis(triphenylphosphine)palladium(0)(0.6 g, 0.5 mmol) in dimethoxyethane:water:ethanol (130 cm³, 10:2:1) washeated to 80° C. for 16 h., then poured into 1 L of water, and extractedwith EtOAc. The organic layer was washed with brine, dried (MgSO₄) andconcentrated. The crude product was subjected to column chromatography(SiO₂, EtOAc:hexane, 1:1) to obtain the title compound (0.9 g, 28%):m.p. 200–203° C.; ¹H NMR (DMSO-d₆) δ 1.63 (m, 8H), 1.87 (m, 2H), 2.27(s, 3H), 6.95 (d, 1H, J=8.13 Hz), 7.34 (dd, 1H, J=8.13, 1.98 Hz), 7.54(d, 1H, J=1.98 Hz), 7.82 (s, 1H), 10.50 (s, 1H); MS ((+)APC1) m/z 323[M+H]⁺.

A solution of4-methyl-5-[2′-oxo-2′3′-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-2-thiophenecarbonitrile(0.61 g, 1.9 mmol) and phosphorous pentasulfide (0.92 g, 2.1 mmol) indioxane (17 mL) was heated to 85° C. for 30 minutes. The reactionmixture was poured into distilled water, and washed with aqueous NaHCO₃,distilled water, dried over MgSO₄, and evaporated to dryness. Theresidue was purified with column chromatography (2.5% MeOH/CH₂Cl₂) toafford the title compound (0.05 g, 8%) as a orange-brown solid: m.p.244–249° C.; ¹H-NMR (DMSO-d₆) δ 12.75 (s, 1H), 9.54 (s, 1H), 9.34 (s,1H), 7.76 (d, 1H, J=1.5 Hz), 7.58 (s, 1H), 7.45 (dd, 1H, J=6.4, 1.8 Hz),7.14 (d, 1H, J=7.9 Hz), 2.26 (s, 3H), 1.98–1.89 (m, 7H), 1.83–1.81 (m,3H); MS ((+)APCI) [M+H]⁺ @ m/z 373.

EXAMPLE 6 PHARMACOLOGY

The progestational activity for the compounds of the current inventionwas evaluated in the in-vitro and in-vivo assays described below.In-vitro potencies lie in the range 0.01 nM–10,000 nM, and in-vivopotencies in the range 1 μg/kg to 30 mg/kg.

A. In-vitro Biology

The in-vitro biology is determined by (1) competitive RadioligandBinding: using the A-form of the human progesterone receptor withprogesterone as the radioligand; (2) co-transfection assay, whichprovides functional activity expressed as agonist EC50 and AntagonistIC50 values; (3) a T47D cell proliferation, which is a furtherfunctional assay which also provides agonist and antagonist data; and(4) T47D cell alkaline phosphatase assay, which is a further functionalassay which also provides agonist and antagonist data.

1. hPR Binding assay—This assay is carried out in accordance with:Pathirana, C.; Stein, R. B.; Berger, T. S.; Fenical, W.; Ianiro, T.;Mais, D. E.; Torres, A.; Glodman, M. E., Nonsteroidal human progesteronereceptor modulators from the marine alga cymoplia barbata, J. SteroidBiochem. Mol. Biol., 1992, 41, 733–738.

2. PRE-luciferase Assay in CV-1 Cells

The object of this assay is to determine a compound's progestational orantiprogestational potency based on its effect on PRE-luciferasereporter activity in CV-1 cells co-transfected with human PR andPRE-luciferase plasmids. The materials methods used in the assay are asfollows.

a. Growth medium: DMEM (BioWhittaker) containing 10% (v/v) fetal bovineserum (heat inactivated), 0.1 mM MEM non-essential amino acids, 100 U/mlpenicillin, 100 mg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL).Experimental medium: DMEM (BioWhittaker), phenol red-free, containing10% (v/v) charcoal-stripped fetal bovine serum (heat-inactivated), 0.1mM MEM non-essential amino acids, 100 U/ml penicillin, 100 mg/mlstreptomycin, and 2 mM GlutaMax (GIBCO, BRL).

b. Cell Culture, Transfection, Treatment, and Luciferase Assay

Stock CV-1 cells are maintained in growth medium. Co-transfection isdone using 1.2×10⁷ cells, 5 mg pLEM plasmid with hPR-B inserted at Sph1and BamH1 sites, 10 mg pGL3 plasmid with two PREs upstream of theluciferase sequence, and 50 mg sonicated calf thymus DNA as carrier DNAin 250 ml. Electroporation is carried out at 260 V and 1,000 mF in aBiorad Gene Pulser II. After electroporation, cells are resuspended ingrowth medium and plated in 96-well plate at 40,000 cells/well in 200μl. Following overnight incubation, the medium is changed toexperimental medium. Cells are then treated with reference or testcompounds in experimental medium. Compounds are tested forantiprogestational activity in the presence of 3 nM progesterone.Twenty-four hr. after treatment, the medium is discarded, cells arewashed three times with D-PBS (GIBCO, BRL). Fifty μl of cell lysisbuffer (Promega, Madison, Wis.) is added to each well and the plates areshaken for 15 min in a Titer Plate Shaker (Lab Line Instrument, Inc.).Luciferase activity is measured using luciferase reagents from Promega.

c. Analysis of Results:

Each treatment consists of at least 4 replicates. Log transformed dataare used for analysis of variance and nonlinear dose response curvefitting for both agonist and antagonist modes. Huber weighting is usedto downweight the effects of outliers. EC₅₀ or IC₅₀ values arecalculated from the retransformed values. JMP software (SAS Institute,Inc.) is used for both one-way analysis of variance and non-linearresponse analyses.

d. Reference Compounds:

Progesterone and trimegestone are reference progestins and RU486 is thereference antiprogestin. All reference compounds are run in fulldose-response curves and the EC₅₀ or IC₅₀ values are calculated.

TABLE 1 Estimated EC₅₀, standard error (SE), and 95% confidenceintervals (CI) for reference progestins from three individual studiesEC50 95% CI Compound Exp. (nM) SE lower upper Progesterone 1 0.616 0.0260.509 0.746 2 0.402 0.019 0.323 0.501 3 0.486 0.028 0.371 0.637Trimegestone 1 0.0075 0.0002 0.0066 0.0085 2 0.0081 0.0003 0.0070 0.00943 0.0067 0.0003 0.0055 0.0082

TABLE 2 Estimated IC₅₀, standard error (SE), and 95% confident interval(CI) for the antiprogestin, RU486 from three individual studies IC 5095% CI Compound Exp. (nM) SE lower upper RU486 1 0.028 0.002 0.019 0.0422 0.037 0.002 0.029 0.048 3 0.019 0.001 0.013 0.027

Progestational activity: Compounds that increase PRE-luciferase activitysignificantly (p<0.05) compared to vehicle control are consideredactive.

Antiprogestational activity: Compounds that decrease 3 nM progesteroneinduced PRE-luciferase activity significantly (p<0.05)

EC₅₀: Concentration of a compound that gives half-maximal increasePRE-luciferase activity (default-nM) with SE.

IC₅₀: Concentration of a compound that gives half-maximal decrease in 3nM progesterone induced PRE-luciferase activity (default-nM) with SE.

3. T47D Cell Proliferation Assay

The objective of this assay is the determination of progestational andantiprogestational potency by using a cell proliferation assay in T47Dcells. A compound's effect on DNA synthesis in T47D cells is measured.The materials and methods used in this assay are as follows.

a. Growth medium: DMEM:F12 (1:1) (GIBCO, BRL) supplemented with 10%(v/v) fetal bovine serum (not heat-inactivated), 100 U/ml penicillin,100 mg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL).

b. Treatment medium: Minimum Essential Medium (MEM) (#51200-038GIBCO,BRL) phenol red-free supplemented with 0.5% charcoal stripped fetalbovine serum, 100 U/ml penicillin, 200 mg/ml streptomycin, and 2 mMGlutaMax (GIBCO, BRL).

c. Cell Culture

Stock T47 D cells are maintained in growth medium. For BrdUincorporation assay, cells are plated in 96-well plates (Falcon, BectonDickinson Labware) at 10,000 cells/well in growth medium. Afterovernight incubation, the medium is changed to treatment medium andcells are cultured for an additional 24 hr before treatment. Stockcompounds are dissolved in appropriate vehicle (100% ethanol or 50%ethanol/50% DMSO), subsequently diluted in treatment medium and added tothe cells. Progestin and antiprogestin reference compounds are run infull dose-response curves. The final concentration of vehicle is 0.1%.In control wells, cells receive vehicle only. Antiprogestins are testedin the presence of 0.03 nM trimegestone, the reference progestinagonist. Twenty-four hours after treatment, the medium is discarded andcells are labeled with 10 mM BrdU (Amersham Life Science, ArlingtonHeights, Ill.) in treatment medium for 4 hr.

d. Cell Proliferation Assay

At the end of BrdU labeling, the medium is removed and BrdUincorporation is measured using a cell proliferation ELISA kit (#RPN250, Amersham Life Science) according to manufacturer's instructions.Briefly, cells are fixed in an ethanol containing fixative for 30 min,followed by incubation in a blocking buffer for 30 min to reducebackground. Peroxidase-labeled anti-BrdU antibody is added to the wellsand incubated for 60 min. The cells are rinsed three times with PBS andincubated with 3,3′5,5′-tetramethylbenzidine (TMB) substrate for 10–20min depending upon the potency of tested compounds. Then 25 μl of 1 Msulfuric acid is added to each well to stop color reaction and opticaldensity is read in a plate reader at 450 nm within 5 min.

e. Analysis of Results:

Square root-transformed data are used for analysis of variance andnonlinear dose response curve fitting for both agonist and antagonistmodes. Huber weighting is used to downweight the effects of outliers.EC₅₀ or IC₅₀ values are calculated from the retransformed values. JMPsoftware (SAS Institute, Inc.) is used for both one-way analysis ofvariance and non-linear dose response analyses in both single dose anddose response studies.

f. Reference Compounds:

Trimegestone and medroxyprogesterone acetate (MPA) are referenceprogestins and RU486 is the reference antiprogestin. All referencecompounds are run in full dose-response curves and the EC₅₀ or IC₅₀values are calculated.

TABLE 3 Estimated EC₅₀, standard error (SE), and 95% confidenceintervals (CI) for individual studies EC₅₀ 95% CI Compound Exp. (nM) SElower upper Trimegestone 1 0.017 0.003 0.007 0.040 2 0.014 0.001 0.0110.017 3 0.019 0.001 0.016 0.024 MPA 1 0.019 0.001 0.013 0.027 2 0.0170.001 0.011 0.024

TABLE 4 Estimated IC₅₀, standard error, and 95% confident interval forthe antiprogestin, RU486 IC₅₀ 95% CI Compound Exp. (nM) SE lower upperRU486 1 0.011 0.001 0.008 0.014 2 0.016 0.001 0.014 0.020 3 0.018 0.0010.014 0.022EC₅₀: Concentration of a compound that gives half-maximal increase inBrdU incorporation with SE; IC₅₀: Concentration of a compound that giveshalf-maximal decrease in 0.1 trimegestone induced BrdU incorporationwith SE

4. T47D Cell Alkaline Phosphatase Assay

The purpose of this assay is to identify progestins or antiprogestins bydetermining a compound's effect on alkaline phosphatase activity in T47Dcells. The materials and methods used in this assay are as follows.

a. Culture medium: DMEM:F12 (1:1) (GIBCO, BRL) supplemented with 5%(v/v) charcoal stripped fetal bovine serum (not heat-inactivated), 100U/ml penicillin, 100 μg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL).

b. Alkaline phosphatase assay buffer: I. 0.1 M Tris-HCl, pH 9.8,containing 0.2% Triton X-100; II. 0.1 M Tris-HCl, pH 9.8 containing 4 mMp-nitrophenyl phosphate (Sigma).

c. Cell Culture and Treatment:

Frozen T47D cells were thawed in a 37° C. water bath and diluted to280,000 cells/ml in culture medium. To each well in a 96-well plate(Falcon, Becton Dickinson Labware), 180 μl of diluted cell suspensionwas added. Twenty μl of reference or test compounds diluted in theculture medium was then added to each well. When testing for progestinantagonist activity, reference antiprogestins or test compounds wereadded in the presence of 1 nM progesterone. The cells were incubated at37° C. in a 5% CO₂/humidified atmosphere for 24 hr.

d. Alkaline Phosphatase Enzyme Assay:

At the end of treatment, the medium was removed from the plate and fiftyμl of assay buffer I was added to each well. The plates were shaken in atiter plate shaker for 15 min. Then 150 μl of assay buffer II was addedto each well. Optical density measurements were taken at 5 min intervalsfor 30 min at a test wavelength of 405 nM.

e. Analysis of Results: Analysis of dose-response data

For reference and test compounds, a dose response curve is generated fordose (X-axis) vs. the rate of enzyme reaction (slope) (Y-axis). Squareroot-transformed data are used for analysis of variance and nonlineardose response curve fitting for both agonist and antagonist modes. Huberweighting is used to downweight the effects of outliers. EC₅₀ or IC₅₀values are calculated from the retransformed values. JMP software (SASInstitute, Inc.) is used for both one-way analysis of variance andnon-linear dose response analyses in both single dose and dose responsestudies.

f. Reference Compounds:

Progesterone and trimegestone are reference progestins and RU486 is thereference antiprogestin. All reference compounds are run in full doseresponse curves and the EC₅₀ or IC₅₀ values are calculated.

TABLE 5 Estimated EC₅₀, standard error (SE), and 95% confidenceintervals (CI) for reference progestins from three independentexperiments EC50 95% CI Compound Exp. (nM) SE lower upper Progesterone 10.839 0.030 0.706 0.996 2 0.639 0.006 0.611 0.669 3 1.286 0.029 1.1581.429 Trimegestone 1 0.084 0.002 0.076 0.091 2 0.076 0.001 0.072 0.080 30.160 0.004 0.141 0.181

TABLE 6 Estimated IC₅₀, standard error, and 95% confident interval forthe reference antiprogestin RU486 from three independent experiments IC50 95% CI Compound Exp. (nM) SE lower upper RU486 1 0.103 0.002 0.0920.115 2 0.120 0.001 0.115 0.126 3 0.094 0.007 0.066 0.134

B. In-vivo Biology

The primary in-vivo assay is the rat decidualization model which may beused to determine progestational effects of both agonists andantagonists. The secondary in-vivo assay is the rat ovulation inhibitionmodel which is under development and hence the protocol is un-available.

1. Rat decidualization assay: The objective of this procedure is used toevaluate the effect of progestins and antiprogestins on rat uterinedecidualization and compare the relative potencies of various testcompounds. The materials and methods used in this assay are as follows.

a. Methods: Test compounds are dissolved in 100% ethanol and mixed withcorn oil (vehicle). Stock solutions of the test compounds in oil(Mazola™) are then prepared by heating (˜80° C.) the mixture toevaporate ethanol. Test compounds are subsequently diluted with 100%corn oil or 10% ethanol in corn oil prior to the treatment of animals.No difference in decidual response was found when these two vehicleswere compared.

b. Animals (RACUC Protocol #5002)

Ovariectomized mature female Sprague-Dawley rats (˜60-day old and 230 g)are obtained from Taconic (Taconic Farms, N.Y.) following surgery.Ovariectomy is performed at least 10 days prior to treatment to reducecirculating sex steroids. Animals are housed under 12 hr light/darkcycle and given standard rat chow and water ad libitum.

c. Treatment

Rats are weighed and randomly assigned to groups of 4 or 5 beforetreatment. Test compounds in 0.2 ml vehicle are administered bysubcutaneous injection in the nape of the neck or by gavage using 0.5ml. The animals are treated once daily for seven days. For testingantiprogestins, animals are given the test compounds and a EC₅₀ dose ofprogesterone (5.6 mg/kg) during the first three days of treatment.Following decidual stimulation, animals continue to receive progesteroneuntil necropsy four days later.

d. Dosing

Doses are prepared based upon mg/kg mean group body weight. In allstudies, a control group receiving vehicle is included. Determination ofdose-response curves is carried out using doses with half log increases(e.g. 0.1, 0.3, 1.0, 3.0 mg/kg . . . ).

e. Decidual Induction

Approximately 24 hr after the third injection, decidualization isinduced in one of the uterine horns by scratching the antimesometrialluminal epithelium with a blunt 21 G needle. The contralateral horn isnot scratched and serves as an unstimulated control. Approximately 24 hrfollowing the final treatment, rats are sacrificed by CO₂ asphyxiationand body weight measured. Uteri are removed and trimmed of fat.Decidualized (D-horn) and control (C-horn) uterine horns are weighedseparately.

f. Analysis of Results:

The increase in weight of the decidualized uterine horn is calculated byD-horn/C-horn and logarithmic transformation is used to maximizenormality and homogeneity of variance. The Huber M-estimator is used todown weight the outlying transformed observations for both dose-responsecurve fitting and one-way analysis of variance. JMP software (SASInstitute, Inc.) is used for both one-way ANOVA and non-lineardose-response analyses.

g. Reference Compounds:

All progestin reference compounds were run in full dose-response curvesand the EC₅₀ for uterine wet weight were calculated.

TABLE 7 Estimated EC₅₀, standard error (SE), and 95% confidenceintervals for individual studies EC₅₀ 95% CI Compound Exp. (mg/kg, s.c.)SE lower upper Progesterone 1 5.50 0.77 4.21 7.20 2 6.21 1.12 4.41 8.763-Ketodesogestrel 1 0.11 0.02 0.07 0.16 2 0.10 0.05 0.11 0.25 3 0.060.03 0.03 0.14 Levonorgestrel 1 0.08 0.03 0.04 0.16 2 0.12 0.02 0.090.17 3 0.09 0.02 0.06 0.13 4 0.09 0.02 0.06 0.14 MPA 1 0.42 0.03 0.290.60 2 0.39 0.05 0.22 0.67 3 0.39 0.04 0.25 0.61

TABLE 8 Estimated average EC₅₀, standard error, and 95% confidenceintervals for dose-response curves of 3 reference compounds EC50 95% CICompound (mg/kg, s.c.) SE lower upper Progesterone 5.62 0.62 4.55 7.003-Ketodesogestrel 0.10 0.02 0.07 0.14 Levonorgestrel 0.10 0.01 0.08 0.12

TABLE 9 Estimated IC₅₀, standard error, and 95% confident interval forthe antiprogestin, RU 486 IC₅₀ 95% CI Compound Exp. (mg/kg, p.o.) SElower upper RU 486 1 0.21 0.07 0.05 0.96 2 0.14 0.02 0.08 0.27

Concentration: Compound concentration in assay (default-mg/kg bodyweight)

Route of administration: Route the compound is administered to theanimals

Body weight: Mean total animal body weight (default-kg)

D-horn: Wet weight of decidualized uterine horn (default-mg)

C-horn: Wet weight of control uterine horn (default-mg)

Decidual response: [(D−C)/C]×100%

Progestational activity: Compounds that induce decidualizationsignificantly (p<0.05) compared to vehicle control are considered active

Antiprogestational activity: Compounds that decrease EC₅₀ progesteroneinduced decidualization significantly (p<0.05)

EC₅₀ for uterine weight: Concentration of compound that giveshalf-maximal increase in decidual response (default-mg/kg)

IC₅₀ for uterine weight: Concentration of compound that giveshalf-maximal decrease in EC₅₀ progesterone induced decidual response(default-mg/kg)

TABLE 10 Data for Representative Compounds Ovulation inhibition Example# Ki/nM CV-1 EC50/nM IC100 mg/kg 5 0.3 3 0.1 0.2 1 0.2 0.8 4 0.06 0.10.1

EXAMPLE 75-(1,2-DIHYDRO-2-THIOXOSPIRO[CYCLOPENTANE-1,3-[3H]INDOL]-5′-YL)-1H-PYRROLE-2-CARBONITRILE

5-(2′-Oxo-2′,3′-dihydrospiro[cyclopentane-1,3′-[3H]indol]-5′-yl-2-cyanopyrrole:A solution of 5′-bromospiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one(2.0 g, 7.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (430 mg,0.3 mmol) in ethylene glycol dimethyl ether (50 mL) was stirred under aflow of nitrogen for 15 min. To the solution was added sequentially1-t-butoxycarbonylpyrrole-2-boronic acid (2.1 g, 9.7 mmol) and potassiumcarbonate (2.4 g, 17 mmol) in water (10 mL). The mixture was heated to80° C. for 3 h and allowed to cool. The reaction mixture was poured intowater (50 mL) and extracted with ethyl acetate (3×50 mL). The organiclayers were combined, washed with brine (30 mL) and dried over magnesiumsulfate. The solution was filtered and concentrated in vacuo.Crystallization from 20% ethyl acetate/hexane gave2-(1′,2′-dihydro-2′-oxospiro[cyclopentane-1,3′-[3H]indol]-5′-yl)-1H-pyrrole-1-carboxylicacid, tert-butyl ester (2.2 g, 83%) as a white powder, mp 179–180.5° C.¹H NMR (DMSO-d₆, 400 MHz) δ 1.30 (s, 9H), 1.75–1.98 (m, 8H), 6.16 (dd,1H, J=1.8, 3.3 Hz), 6.22 (‘t’, 1 H, J=3.3, 3.3 Hz), 6.79 (d, 1 H, J=7.9Hz), 7.08 (dd, 1 H, J=1.8, 7.9 Hz), 7.14 (‘d’, 1 H, J=1.5 Hz), 7.28 (dd,J=1.9, 3.3 Hz), 10.30 (s, 1 H). MS (EI) m/z 352 [M⁺]. Anal. Calcd forC₂₁H₂₄N₂O₃: C, 71.57; H, 6.86; N, 7.95. Found: C, 71.08; H, 6.83; N,7.74.

To a solution of2-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-1H-pyrrole-1-carboxylicacid, tert-butyl ester (2.2 g, 6.0 mmol) in THF (anhydrous, 25 mL) wasadded at −78° C. chlorosulfonyl isocyanate (0.63 mL, 7.0 mmol). After 90min, dimethylformamide (11 mL, 140 mmol) was added and the reaction wasallowed to warm to room temperature. The reaction mixture was pouredinto water (50 mL) and extracted with ethyl acetate (2×50 mL). Theorganic layers were combined, washed with brine (50 mL), dried overmagnesium sulfate, filtered and concentrated in vacuo. Purification viaflash column chromatography on silica gel (30% ethyl acetate/hexane)gave5-(2′-oxo-2′,3′-dihydrospiro[cyclopentane-1,3′-[3H]indol]-5′-yl-2-cyanopyrrole-1-carboxylicacid, tert-butyl ester (1.7 g, 75%) as white crystals, mp 167–9° C. ¹HNMR (DMSO-d₆, 400 MHz) δ 1.34 (s, 9H), 1.75–1.98 (m, 8 H), 6.39 (d, 1 H,J=3.7 Hz), 6.84 (d, 1H, J=7.9 Hz), 7.17 (dd, 1 H, J=1.8, 7.9 Hz), 7.28(‘t’, 2 H), 10.41 (s, 1 H). MS (ESI) m/z 376 [M−H]⁻. Anal. Calcd. forC₂₂H₂₃N₃O₃: C, 70.01; H, 6.14; N, 11.13. Found: C, 69.67; H, 6.38; N,11.04.

5-(2′-Oxo-2′,3′-dihydrospiro[cyclopentane-1,3′-[3H]indol]-5′-yl-2-cyanopyrrole-1-carboxylicacid, tert-butyl ester (1 g, 2.7 mmol) was placed in a 25 mL roundbottomed flask stoppered with a rubber septum and equipped with nitrogeninlet and a needle to allow gaseous outflow. A vigorous flow of nitrogenwas maintained as the flask was placed in an oil bath and heated to 165°C. After 20 min at this temperature, the flask was removed from the oilbath and allowed to cool. Crystallization from ethyl ether gave thetitle compound (600 mg, 79%) as a yellow powder, mp 285–286° C. ¹H NMR(DMSO-d₆, 400 MHz) δ 1.75–2.03 (m, 8 H), 6.60 (dd, 1 H, J=2.4, 3.7 Hz),6.84 (d, 1 H, J=8.1 Hz), 6.94 (dd, 1 H, J=2.4, 3.7 Hz), 7.52 (dd, 1 H,J=1.8, 8.1 Hz), 7.60 (d, 1 H, J=1.8 Hz), 10.38 (s, 1 H), 12.45 (s, 1 H).MS (ESI) m/z 276 [M−H]⁻. Anal. Calcd. For C₁₇H₁₅N₃O: C, 73.63; H, 5.45;N, 15.15. Found: C, 73.24; H, 5.34; N, 14.96.

To5-(1,2-Dihydro-2-oxospiro[cyclopentane-1,3-[3H]indol]-5′-yl)-1H-pyrrole-2-carbonitrile(0.18 g, 0.7 mmol, 1 eq) in p-xylene (20 mL) was added Lawesson'sreagent (0.14 g, 0.36 mmol, 0.5 eq) and the reaction was heated toreflux for 1 hour. The reaction was cooled to room temperature andadsorbed onto silica gel. Purification by flash column chromatography(20% ethyl acetate/hexane) on silica gel gave the product as an orangepowder. Further purification by HPLC gave the title compound as a greensolid (0.144 g, 70%), mp 275–276° C. (dec.). ¹H NMR (d₆-DMSO, 300 MHz) δ1.81–2.16 (m, 8 H), 6.69 (dd, 1H, J=2.3, 3.7 Hz), 6.98 (dd, 1 H, J=1.8,3.7 Hz), 7.04 (d, 1 H, J=8.2 Hz), 7.63 (dd, 1 H, J=1.6, 8.2 Hz), 7.72(d, 1 H, J=1.3 Hz), 12.57 (s, 1 H), 12.65 (s, 1 H). MS (ESI) [M−H]⁻=292.Anal. Calculated (cald.) for C₁₇H₁₅N₃S: C, 69.6; H, 5.15; N, 14.32.Found: C, 69; H, 5.31; N, 13.81.

EXAMPLE 85-(1,2-DIHYDRO-2-THIOXOSPIRO[CYCLOHEXANE-1,3-[3H]INDOL]-5-YL)-1-(TERT-BUTOXYCARBONYL)-PYRROLE-2-CARBONITRILE

To a solution of 5′-bromo-spiro[cyclohexane-1,3′-indolin]-2′-one (3.4 g,12 mmol) in 1,2-DME (100 mL) under a nitrogen atmosphere was addedtetrakis(triphenylphospine)palladium(0) (70 mg, 5 mol %). After 15 min,2-borono-1H-pyrrole-1-carboxylic acid, 1-tert butyl ester (1.3 eq, 3.31g, 15.6 mmol) and a solution of K₂CO₃ (2.3 eq, 3.83 g, 27.6 mmol) inwater (5 mL) were added sequentially. The solution was heated to 80° C.for 3 h and allowed to cool. The reaction mixture was poured into water(200 mL) and extracted with EtOAc (2×100 mL). The organic layers werecombined, washed with brine (150 mL) and dried over MgSO₄. The solutionwas filtered, concentrated in vacuo, and the residue was purified byflash column chromatography on silica gel (eluting with 30%EtOAc/hexane) to give2-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-1H-pyrrole-1-carboxylicacid, tert-butyl ester (3.4 g, 76%) as a white powder, mp 177° C. ¹H NMR(CDCl₃; 300 MHz) δ 1.38 (s, 9 H), 1.59–1.93 (m, 10 H), 6.18 (m, 1 H),6.23 (‘t’, 1H, 3 Hz), 6.91 (d, 1H, J=8 Hz), 7.21 (d, 1 H, J=8 Hz), 7.34(m, 1 H), 7.44 (s, 1 H), 8.33 (br s, 1 H, D₂Oex). MS ((+)-APCI) m/z 367[(M+H)⁺]. Anal. Calcd for C₂₂H₂₆N₂O₃: C, 72.11; H, 7.15; N, 7.64. Found:C, 71.7; H, 7.16; N, 7.5.

To a solution of2-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-1H-pyrrole-1-carboxylicacid, tert-butyl ester (0.75 g, 2 mmol) in THF (anhydrous, 20 mL) at−78° C. was added chlorosulfonyl isocyanate (1.15 eq, 0.23 mL, 2.3mmol). After 90 min, DMF (20 eq, 3.6 mL, 46 mmol) was added and thereaction was allowed to warm to room temperature. The reaction mixturewas poured into water (50 mL) and extracted with ethyl acetate (2×50mL). The organic layers were combined, washed with brine (50 mL), driedover magnesium sulfate, filtered and concentrated in vacuo. Purificationvia flash column chromatography on silica gel (30% ethyl acetate/hexane)gave5-(2′-oxo-2′,3′-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl-2-cyanopyrrole-1-carboxylicacid, tert-butyl ester (0.5 g, 63%) as an oil which crystallized fromacetone to give white crystals, mp 156° C. ¹H NMR (d₆-DMSO, 400 MHz) δ1.32 (s, 9H), 1.50 (m, 3 H), 1.60–1.70 (m, 5 H), 1.75–1.85 (m, 2 H),6.38 (d, 1 H, J=3.7 Hz), 6.87 (d, 1 H, J=7.9 Hz), 7.18 (dd, 1 H, J=1.5,7.9 Hz), 7.27 (d, 1 H, J=3.7 Hz), 7.48 (d, 1 H, J=1.8 Hz), 10.42 (bs, 1H). MS (EI) m/z 391 (M⁺). Anal. Calcd for C₂₃H₂₅N₃O₃: C, 70.57; H, 6.44;N, 10.73. Found: C, 69.82; H, 6.46; N, 10.43.

To a solution of2-Cyano-5-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1H-pyrrole-1-carboxylicacid, tert-butyl ester (0.7 g, 1.8 mmol, 1 eq) in toluene (70 mL) wasadded Lawesson's reagent (0.47 g, 1.1 mmol, 0.65 eq) and the reactionwas heated to reflux for 1 hour. The reaction was cooled to roomtemperature, poured into water (100 mL) and extracted with ethyl acetate(2×100 mL). The organic layers were combined, washed with brine (50 mL),dried over magnesium sulfate, filtered and concentrated in vacuo.Purification by flash column chromatography (20–30% ethylacetate/hexane) on silica gel gave title compound as a yellow solid (0.7g, 96%). ¹H NMR (d₆-DMSO, 500 MHz) δ 1.30–1.98 (m, 19 H), 6.45 (d, 1 H,J=3.7 Hz), 7.09 (d, 11 H, J=7.9 Hz), 7.31–7.34 (m, 2 H), 7.81 (d, 1 H,J=1.4 Hz), 12.74 (s, 1 H). MS (ESI) [M−H]⁻=406. Anal. calcd. forC₂₃H₂₅N₃O₂S: C, 67.79; H, 6.18; N, 10.31. Found: C, 67.86; H, 5.99; N,10.25.

EXAMPLE 95-(1,2-DIHYDRO-2-THIOXOSPIRO[CYCLOHEXANE-1,3-[3H]INDOL]-5-YL)-1-H-PYRROLE-2-CARBONITRILE

To a solution of5-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1-(tert-butoxycarbonyl)-pyrrole-2-carbonitrile(0.5 g, 1.2 mmol, 1 eq) in THF (5 mL) was added NaOEt (0.25 g, 3.6 mmol,3 eq) in EtOH (5 mL) and the reaction was heated to 80° C. for 24 h. Thesolvents were removed in vacuo and the residue partitioned between ethylacetate (50 mL) and water (50 mL). The layers were separated and theaqueous layer was extracted with ethyl acetate (50 mL). The organiclayers were combined, washed with brine (50 mL), dried over magnesiumsulfate, filtered and concentrated in vacuo. Purification by flashcolumn chromatography (30% ethyl acetate/hexane) on silica gel gave thetitle compound (0.27 g, 68%) as a yellow powder. ¹H NMR (d₆-DMSO, 500MHz) δ 1.32–1.99 (m, 10 H), 6.71 (d, 1 H, J=3.7 Hz), 7.00 (d, 1H, J=3.7Hz), 7.09 (d, 1 H, J=8.4 Hz), 7.70 (dd, 1 H, J=1.6, 8.4 Hz), 8.05 (d, 1H, J=1.1 Hz), 12.67 (s, 1 H), 12.73 (s, 1 H). MS (ESI) [M−H]⁻=306. Anal.calcd. for C₁₈H₁₇N₃S: C, 70.33; H, 5.57; N, 13.67. Found: C, 69.64; H,5.79; N, 13.04.

EXAMPLE 105-(2′-THIOXOSPIRO[CYCLOHEXANE-1,3′-[3H]INDOL]-5′-YL)-1-METHYL-PYRROLE-2-CARBONITRILE

To a solution of5-(2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-1-methyl-pyrrole-2-carbonitrile(0.55 g, 1.8 mmol, 1 eq) in toluene (50 mL) was added Lawesson's reagent(0.47 g, 1.1 mmol, 0.65 eq) and the reaction was heated to 80° C. for 1hour. The reaction was cooled to room temperature, poured into water(100 mL) and extracted with ethyl acetate (2×100 mL). The organic layerswere combined, washed with brine (50 mL), dried over magnesium sulfate,filtered and concentrated in vacuo. Purification by flash columnchromatography on silica gel gave the product as a white solid (0.32 g,55%). ¹H NMR (d₆-DMSO, 500 MHz) δ 1.36–1.99 (m, 10 H), 3.7 (s, 3 H),6.35 (d, 1 H, J=4.2 Hz), 7.05 (d, 1 H, J=4.2 Hz), 7.16 (d, 1 H, J=7.9Hz), 7.44 (dd, 1 H, J=1.6, 8.1 Hz), 7.83 (d, 1 H, J=1.6 Hz), 12.75 (s, 1H). MS (ESI) [M−H]⁻=320. Anal. calcd. for C₁₉H₁₉N₃S: C, 70.99; H, 5.96;N, 13.07. Found: C, 68.69; H, 5.36; N, 12.27.

EXAMPLE 115-(1,2-DIHYDRO-2-THIOXOSPIRO[CYCLOPENTANE-1,3-[3H]INDOL]-5-YL)-3-THIOPHENECARBONITRILE

5-Bromo-2-thiophenecarbonitrile: A mixture of5-bromo-2-thiophenecarboxaldehyde (96.0 g, 500 mmol), hydroxylaminehydrochloride (111.9 g, 500 mmol), pyridine (500 mL), and ethanol (500mL) was heated under nitrogen at reflux for two hours. The reactionmixture was cooled to ambient temperature and concentrated in vacuo togive an oil. The crude product was triturated twice with ice water andthe solid obtained was collected on a filter. A mixture of a portion ofthe above solid (44.31 g, 215 mmol), copper(II)acetate monohydrate (4.2g, 21 mmol) in acetonitrile (1.4 L) was heated at reflux for threehours. The solvent was removed in vacuo and the residue was dissolved inethyl acetate. The solution was washed with 5% aqueous sulfuric acid(2×30 mL), water (2×30 mL), brine (20 mL), and dried (MgSO₄). Thesolvent was removed in vacuo and the residue was dissolved in a minimumamount of chloroform (1 L) and allowed to crystallize. The crystalobtained was collected on a filter and the filtrate was concentrated andpurified by a chromatography (silica gel, chloroform) to give thesubtitled compound as an off-white solid (31.5 g combined, 58%). IR(film) 2200 cm⁻¹. ¹H-NMR (CDCl₃) δ 7.39–7.38 (d, 1H, J=4.1 Hz), 7.10 (d,1H, J=4.0 Hz); MS (EI) m/z 187 (M⁺, 98%) 189(M⁺, 100%).

5-(1,2-dihydro-2-oxospiro[cyclopentane-1,3-[3H]indole]-5-yl)-3-thiophenecarbonitrilewas prepared according to the procedure for Example 5 using5-bromo-2-thiophenecarbonitrile and(2′-oxo-2′,3′-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)boronicacid: mp. 225–228° C.; ¹H NMR (DMSO-d₆) δ 1.63 (m, 8H), 1.90 (m, 2H),6.91 (d, 1H, J=8.13 Hz), 7.55 (dd, 1H, J=8.13, 1.76 Hz), 7.60 (d, 1H,J=4.17 Hz), 7.75 (d, 1H, J=1.76 Hz), 7.93 (d, 1H, J=4.17 Hz), 10.51 (s,1H); MS ((+)APC1) m/z 309 [M+H]⁺.

A solution of5-(1,2-dihydro-2-oxospiro[cyclopentane-1,3-[3H]indole]-5-yl)-3-thiophenecarbonitrile(0.66 g, 2.4 mmol), and2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide(0.97 g, 2.4 mmol) in toluene (250 ml) was stirred at 80° C. for 2hours. The solution was concentrated in vacuo. The residue was extractedwith ethylacetate, the ethylacetate solution was washed with water,dried over magnesium sulfate, and concentrated. The residue was purifiedby column chromatography (silica gel, ethylacetate, hexane 20/80) toafford the title compound, m.p. 269–272° C. (0.24 g, 32%). ¹H-NMR(DMSO-d₆) δ 2.09 (m, 8H), 7.05 (d, J=8.1 Hz, 1H), 7.55 (dd, J=8.1, 1.7Hz, 1H), 7.7 (d, J=1.7 Hz, 1H), 7.95 (d, J=1.3 Hz, 1H), 8.49 (d, J=1.3Hz, 1H), 8.49 (d, J=1.3 Hz, 1H), 12.68 (s, 1H); MS (EI NEG) m/z 309(M−H)⁻.

EXAMPLE 125-(1,2-DIHYDRO-THIOXOSPIRO(CYCLOPENTANE-1,3-[3H]INDOL)-5-YL)-2-THIOPHENECARBONITRILE

The title compound was prepared from5-(1,2-dihydro-oxospiro(cyclopentane-1,3-[3H]indol)-5-yl)2-thiophenecarbonitrile(2 g, 6.8 mmol) and Lawesson's reagent (3.32 g, 8.2 mmol) heated toreflux in toluene (150 mL) for 3 hours. Yield 1.5 g (48.3%). m.p.250–253° C. ¹H NMR (DMSO-d₆) δ 12.75 (s, 1H), 7.98–7.97 (d, 1 H, J=3.9Hz), 7.71–7.70 (d, 1 H, J=5.2 Hz), 7.65–7.62 (d, 1 H, J=8.1 Hz),7.09–7.07 (d, 1 H, J=8.1 Hz), 2.13–2.08 (m, 6 H), 1.99–1.85 (m, 2 H);MS. [M−H]⁻=309 IR (SP ATR) 1430, 1620, 2220 cm⁻¹. Anal. calc. forC₁₇H₁₄N₂S₂. C, 65.77; H, 4.55; N, 9.02. obs'd C, 65.27; H, 4.41; N,8.84.

EXAMPLE 135-(3-FLUORO-4-METHOXYPHENYL)SPIRO[CYCLOHEXANE-1,3-[3H]INDOLE]-2(1H)-THIONE

5-(3-Fluoro-4-methoxyphenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one:Prepared from 4-bromo-2-fluoroanisole and(2′-oxo-2′,3′-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)boronicacid according to the procedure for example 5 to afford the subtitledcompound as a white solid, mp. 178–180° C.; ¹H-NMR (DMSO-d₆) δ 10.4 (s,1H), 7.65 (d, 1H, J=1.1 Hz), 7.5–7.4 (m, 3H), 7.2 (t, 1H, J=8.8 Hz), 3.9(s, 3H), 1.9 (m, 2H), 1.7–1.6 (m, 8H); MS (APCI (−)) m/z 324 [M−H]⁻;Anal. Calc. For C₂₀H₂₀FNO₂.: C, 73.83, H, 6.20, N, 4.30. Found: C,73.55, H, 6.23, N, 4.40.

The title compound was prepared by refluxing overnight a mixture of5-(3-Fluoro-4-methoxyphenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-oneand an equal weight of phosphorus pentasulfide in pyridine. Removal ofthe pyridine in vacuo followed by treatment of the residue with 5Nhydrochloric acid solution and subsequent recrystallization in ethanolgave a grey solid, mp 228–229° C.; ¹H-NMR (DMSO-d₆) δ 12.7 (s, 1H), 7.9(s, 1H), 7.6–7.5 (m, 2H), 7.5–7.4 (m, 1H), 7.2 (t, 1H, J=8.8 Hz), 7.1(d, 1H, J=8.1 Hz), 3.9 (s, 3H), 1.9–1.8 (m, 7H), 1.4–1.3 (m, 3H); MS(APCI (−)) [M−H]⁻ m/z 324. Anal. Cal. for C₂₀H₂₀FNOS.0.25H₂O, 69.44; H,5.97; N, 4.05. Found: C, 69.43; H, 5.75; N, 4.32.

EXAMPLE 145-(2-AMINO-5-PYRIMIDINYL)SPIRO[CYCLOHEXANE-1,3-[3H]INDOLE]-2(1H)-THIONE

Prepared by refluxing overnight a mixture of5-(2-amino-5-pyrimidinyl)spiro[cyclohexane-1,3-[3H]-indole]-2(1H)-oneand an equal weight of phosphorus pentasulfide in pyridine. Removal ofthe pyridine in vacuo followed by treatment of the residue with 5Nhydrochloric acid solution and subsequent recrystallization in ethanolgave a grey solid; mp 274–277° C. (dec.); ¹H-NMR (DMSO-d₆) δ 12.7 (s,1H), 8.6 (s, 2H), 7.9 (s, 1H), 7.5 (d, 1H, J=8.1 Hz), 7.1 (d, 1H, J=8.1Hz), 6.8 (s, 2H), 1.9–1.8 (m, 7H), 1.4–1.3 (m, 3H). MS (APCI (−)) [M−H]⁻m/z 309.

EXAMPLE 153-(1,2-DIHYDRO-2-THIOXOSPIRO[CYCLOPENTANE-1,3-[3H]INDOL]-5-YL)-5-FLUOROBENZONITRILE

Spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one

To a −25° C. solution of oxindole (2.0 g, 15.0 mmol) in 40 (cm³) ofanhydrous THF under N₂ was added n-butyllithium (1.6 M in hexanes, 19.7cm³, 31.5 mmol) drop-wise. To the resulting milky solution was addedN,N,N′,N′-tetramethylethylenediamine (4.75 cm³, 31.5 mmol). After 30min. a solution of 1,4-diiodobutane (21.9 g, 70.6 mmol) in THF (3 cm³)was added and the reaction mixture was allowed to warm to RT and stirredfor 14 h. The reaction mixture was poured into water, extracted withEtOAc (×2), the combined organic layers were washed with dilute HCl(pH 1) and water (×2), dried (MgSO₄) and evaporated. The residue waspurified by column chromatography (SiO₂, EtOAc:hexane 1:4) to afford thesubtitled compound (1.4 g, 7.5 mmol, 50%) as a tan solid: ¹H NMR (CDCl₃)δ 1.8–2.2 (m, 8H), 6.94 (dd, J=7.5, 1.0 Hz, 1H), 7.01 (dd, J=7.5, 1.0Hz, 1H), 7.14–7.25 (m, 2H), 9.30 (br s, 1H).

5-Bromo-spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one

A solution of spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one (0.27 g,1.4 mmol) and sodium acetate (0.12 g, 1.46 mmol) in acetic acid (10 cm³)was treated with bromine (0.24 g, 1.51 mmol) in acetic acid (2 cm³).After 30 min. the mixture was poured into sat. sodium hydrogen carbonatesolution and extracted with EtOAc (×2), the combined organic layers werewashed with water, sat. sodium hydrogen carbonate solution, water, dried(MgSO₄), and evaporated to give the subtitled compound (0.37 g, 1.47mmol, 96%) as an off-white solid which was used without furtherpurification: ¹H NMR (CDCl₃) δ 1.8–2.27 (m, 8H), 6.79 (d, J=8 Hz, 1H),7.30–7.39 (m, 2H), 8.63 (br s, 1H).

5′-(3-Cyano-5-fluorophenyl)-spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one

A solution of 3-cyano-5-fluoro-bromobenzene (0.5 g, 2.6 mmol), andtetrakis (triphenylphosphine)palladium(0) (0.2 g) in ethylene glycoldimethyl ether (20 cm³) was stirred under N₂ for 20 minutes. To thismixture was then added(spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid (0.9g, 3.9 mmol) and sodium carbonate (0.8 g, 7.8 mmol) in water (5 cm³).The solution was brought to reflux for 18 hours and then cooled to roomtemperature, poured into 2N NaOH and extracted with EtOAc (×3). Thecombined extracts were washed with water, brine, dried (MgSO₄), andevaporated. The residue was purified by column chromatography (SiO₂,EtOAc, hexane) to afford the subtitled compound (0.35 g, 44%) as whiteneedles. mp: 235–237° C.; ¹H NMR (DMSO-d₆) δ 10.5 (s, 1H), 8.1 (s, 1H),8.0 (dt, 1H, J=1.7, 2.0, 7.0 Hz), 7.8–7.7 (m, 2H), 7.6 (dd, 1H, J=1.8,6.4 Hz), 6.9 (d, 1H, J=8.1 Hz), 2.0–1.9 (m, 8H); MS (EI) M⁺ @ m/z 306.

General Procedure A

The title compound was prepared from5′-(3-Cyano-5-fluorophenyl)-spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one(40 mg) and Lawesson's reagent (50 mg) in toluene (10 ml) at reflux in asealed tube for 16 h. The mixture was concentrated and the residuedissolved in a minimal amount of THF, then purified by HPLC (SiO₂, 30cm×2.5 cm, EtOAc-Hexane 2:8 at 20 ml/min.) to afford the title compound(0.022 g) as an off white solid: mp. 236–238° C.; ¹H NMR (DMSO-d₆) δ12.66 (br s, 1H), 8.11 (s, 1H), 7.97 (dt, 1H, J=10.1 and 2.2 Hz),7.79–7.76 (m, 2H), 7.68 (dd, 1H, J=8.1 and 1.7 Hz), 7.07 (d, 1H, J=8.1Hz), 2.10–2.05 (m, 6H) and 1.97–1.88 (m, 2H); MS (EI) m/z 322 [M]⁺.

EXAMPLE 165-(3-CHLOROPHENYL)-3,3-DIMETHYL-1,3-DIHYDRO-2H-INDOLE-2-THIONE

5-(3-Chloro-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one

5-bromo-1,3-dihydro-3,3-dimethyl-2H-indol-2-one (0.98 g, 4.07 mol) andtetrakis(triphenylphosphine)palladium(0) (0.239 g) were stirred under anatmosphere of nitrogen in dimethoxyethane (35 cm³). After 15 min.,3-chlorophenylboronic acid (1.27 g, 8.13 mol) was added, followed bypotassium carbonate (3.40 g, 45 mmol) in water (15 cm³). The reactionwas heated to reflux for 2 hours and then stirred at room temperatureovernight. The mixture was diluted with sat. ammonium chloride andextracted with EtOAc (×3). The combined organic layers were dried(MgSO₄), filtered, and evaporated. The residue was purified by columnchromatography (SiO₂, EtOAc:hexane, 1:3) to afford the subtitledcompound (0.284 g, 25%): mp 188–189° C.; ¹H NMR (DMSO-d₆) δ 3.34 (s, 6H), 6.93 (d, 1 H, J=8.04 Hz), 7.38–7.35 (m, 1 H), 7.53–7.43 (m, 2 H),7.61 (d, 1 H, J=7.68 Hz), 7.70 (s, 2 H), 10.40 (s, 1 H); IR (KBr) 3420,3150, 3050, 1700 cm⁻¹; MS (EI) m/z 270 (M−H)⁻; CHN calculated forC₁₆H₁₄ClNO+0.1 C₄H₈O₂: C, 70.21; H, 5.32; N, 4.99. Found: C, 70.3; H,5.44; N, 4.93.

The title compound was prepared from5-(3-Chloro-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one (100 mg) andLawesson's reagent (120 mg) in toluene (10 ml) at reflux, according toGeneral Procedure A, to afford the title compound (0.031 g) as an offwhite solid: mp. 158–160° C.; ¹H NMR (CDCl₃) δ 9.67 (br s, 1H), 7.55 (s,1H), 7.47–7.43 (m, 3H), 7.40–7.30 (m, 2H), 7.08 (d, 1H, J=8.7 Hz) and1.50 (s, 6H); MS (EI) m/z 287/289 [M]⁺.

EXAMPLE 173-BENZYL-5-(3-CHLOROPHENYL)-3-METHYL-1,3-DIHYDRO-2H-INDOLE-2-THIONE

The title compound was prepared from3-benzyl-5-(3-chloro-phenyl)-3-methyl-1,3-dihydro-indol-2-one (100 mg)and Lawesson's reagent (120 mg) in toluene (10 ml) at reflux, accordingto General Procedure A, to afford the title compound (0.022 g) as an offwhite solid: mp. 168–170° C.; ¹H NMR (CDCl₃) δ 9.23 (br s, 1H), 7.49 (s,1H), 7.49–7.30 (m, 4H), 7.21 (s, 1H), 7.15–7.09 (m, 3H), 6.96–6.94 (m,2H), 6.89 (d, 1H, J=8.0 Hz), 3.19 (dd, 2H, J=40.5 and 13 Hz) and 1.57(s, 3H); MS (EI) m/z 363/365 [M]⁺.

EXAMPLE 184-(3,3-DIMETHYL-2-THIOXO-2,3-DIHYDRO-1H-INDOL-5-YL)-2-FURONITRILE

4-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-furan-2-carbonitrile

Prepared according to the procedure for Example 5 using(2′-oxo-[2,3-dihydro-3,3-dimethyl-1,3′-[3H]indol]-5′-yl)boronic acid(354 mg, 1.7 mmol) and 4-bromo-furan-2-carbonitrile (200 mg, 1.2 mmol)to afford the subtitled compound (76 mg, 0.3 mmol, 26%) as a whitesolid: mp. 199.6–201.4° C., ¹H NMR (DMSO-d₆) δ 1.28 (s, 6H), 6.89 (d,J=8.0 Hz, 1H), 7.48 (dd, J=8.0, 1.8 Hz, 1H), 7.65 (d, J=1.5 Hz, 1H), 8.1(s, 1H), 8.5 (s, 1H), 10.46 (s, 1H); MS (ESI) m/z 251 (M−H)⁻; Anal.C₁₅H₁₂N₂O₂.0.6H₂O

The title compound was prepared from4-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-furan-2-carbonitrile(73 mg) and Lawesson's reagent (120 mg) in toluene (10 ml) at reflux,according to General Procedure A, to afford the title compound (0.003 g)as an off white solid: mp. 188–191° C.; ¹H NMR (CDCl₃) δ 9.63 (br s,1H), 7.83 (s, 1H), 7.36–7.33 (m, 3H), 7.06 (d, 1H, J=7.9 Hz) and 1.48(s, 6H); MS (EI) m/z 268 [M]⁺.

EXAMPLE 195-(3-METHOXYPHENYL)-3,3-DIMETHYL-1,3-DIHYDRO-2H—INDOLE-2-THIONE

5-bromo-1,3-dihydro-3,3-dimethyl-2H-indol-2-one:3,3-dimethyl-indol-2-one (0.65 g, 4.03 mmol) and sodium acetate (0.33 g,4.07 mmol) were stirred in acetic acid (5 cm³) then bromine (0.66 g,4.13 mmol) in acetic acid (5 cm³) was added drop-wise to the reactionmixture. The reaction was stirred for 50 min., then poured into water.The mixture was basified with sodium carbonate, extracted with ethylacetate (×3), dried (MgSO₄), filtered, and evaporated to give thesubtitled compound (0.89 g, 92%) ¹H NMR (DMSO-d₆) δ 1.21 (s, 6 H), 6.76(d, 1 H, J=8.22 Hz), 7.29 (dd, 1 H, J=2.12 Hz, 8.23 Hz), 7.49 (d, 1 H,J=2.03 Hz), 10.4 (s, 1H).

5-bromo-1,3-dihydro-3,3-dimethyl-2H-indol-2-one (0.33 g, 1.38 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.094 g) were stirred under anatmosphere of nitrogen in dimethoxyethane (12 cm³). After 15 minutes,3-methoxyphenylboronic acid (0.42 g, 2.76 mmol) was added, followed bypotassium carbonate (1.15 g, 8.34 mmol) in water (5 cm³). The reactionwas heated to reflux for 5 hours, and then cooled to room temperature.Saturated aqueous ammonium chloride and EtOAc were added and the mixturewas filtered. The aqueous layer was extracted with EtOAc (×2), and thecombined organic layers were dried (MgSO₄), filtered, and evaporated.The residue was purified by column chromatography (SiO₂, EtOAc:hexane1:3) to afford 5-(3-methoxy-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one(0.11 g, 31%), mp=157–158° C.; ¹H NMR (DMSO-d₆) δ 3.34 (s, 6 H), 3.82(s, 3 H), 6.87–6.93 (m, 2 H), 7.20–7.15 (m, 2 H), 7.37–7.32 (m, 1 H),7.49–7.46 (m, 1 H), 7.63 (d, 1 H, J=1.14 Hz), 10.4 (s, 1 H); MS (EI) m/z266 (M−H)⁻; CHN calculated for C₁₇H₁₇NO₂: C, 76.38; H, 6.41; N, 5.24.Found: C, 76.02; H, 6.49; N, 5.02.

The title compound was prepared from5-(3-methoxy-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one (100 mg) andLawesson's reagent (120 mg) in toluene (10 ml) at reflux, according toGeneral Procedure A, to afford the title compound (0.022 g) as an offwhite solid: mp. 149–150° C.; ¹H NMR (CDCl₃) δ 9.69 (br s, 1H),7.49–7.46 (m, 2H), 7.37 (t, 1H, J=8.0 Hz), 7.16 (d, 1H, J=7.7 Hz),7.09–7.06 (m, 2H), 6.90 (dd, 1H, J=8.2 and 2.3 Hz), 3.88 (s, 3H) and1.50 (s, 6H); MS (EI) m/z 283 [M]⁺.

EXAMPLE 203-(1,2-DIHYDRO-2-THIOXOSPIRO[CYCLOHEXANE-1,3-[3H]INDOL]-5-YL)-4-FLUOROBENZONITRILE

3-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-4-fluorobenzonitrile

Prepared according to the procedure for Example 5: m.p. 205–206° C. ¹HNMR (DMSO-d₆) δ 10.47 (s, 1H), 8.08–8.06 (dd, 1H), 7.89–7.85 (m, 1H),7.65 (s, 1H), 7.54–7.49 (m, 1H), 7.43–7.40 (tt, 1H), 6.95–6.93 (d, 1HJ=7.9 Hz), 1.97–1.83 (m, 2H), 1.69–1.55 (m, 8H); MS (EI) m/z 320 (M⁺).

The title compound was prepared from3-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-4-fluorobenzonitrile(100 mg) and Lawesson's reagent (120 mg) in toluene (10 ml) at reflux,according to General Procedure A, to afford the title compound (0.037 g)as an off white solid: mp. 230–233° C.; ¹H NMR (CDCl₃) δ 9.82 (br s,1H), 7.86 (s, 1H), 7.77 (dd, 1H, J=7.0 and 1.8 Hz), 7.68–7.63 (m, 1H),7.45 (d, 1H, J=8.0 Hz), 7.31 (d, 1H, J=9.0 Hz), 7.15 (d, 1H, J=8.1 Hz),2.17–1.84 (m, 7 H) and 1.60–1.54 (m, 3H); MS (EI) m/z 336 [M]⁺.

EXAMPLE 215-(1,2-DIHYDRO-2-THIOXOSPIRO[CYCLOHEXANE-1,3-[3H]INDOL]-5-YL)-3-PYRIDINECARBONITRILE

A solution of 3-bromopyridine-5-carbonitrile (2.79 g, 15.26 mmol),hexamethylditin (5.00 g, 15.26 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.20 g, 0.17 mmol) inanhydrous dimethoxyethane (30 cm³) under N₂ was heated under reflux.After 16 h the mixture was concentrated and purified by columnchromatography (SiO₂, EtOAc:hexane 5:95) to afford3-cyanopyridine-5-trimethylstannane (2.82 g, 10.55 mmol, 69%): ¹H NMR(CDCl₃) δ 0.40 (s, 9H), 8.01 (m, 1H), 8.80 (m, 2H); MS ((+) APCI) m/z269 (M+H)⁺.

A solution of 5′-bromospiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one(1.97 g, 7.05 mmol), 3-cyanopyridine-5-trimethylstannane (2.26 g, 8.46mmol), bis(triphenylphosphine)palladium(II)chloride (0.33 g, 0.47 mmol)and lithium chloride (1.48 g, 35 mmol) in anhydrous toluene (30 cm³) washeated under reflux. After 16 h the mixture was cooled, partitionedbetween EtOAc and water, the aqueous layer was re-extracted with EtOAc(×2), the combined organic extracts were washed with water, dried(MgSO₄) and evaporated. The residue was subjected to columnchromatography (SiO₂, EtOAc:hexane, 1:2) and then further purified bypreparative LC (Primesphere C18, 10 micron, 50×250 mm, MeCN:H₂O 1:1, 100cm³/min., RT 7.92 min.) to afford3-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol-5′-yl)pyridinecarbonitrile, as white crystals (0.56 g, 1.84 mmol, 26%): mp. 232–234°C., ¹H NMR (CDCl₃) δ 1.68–1.89 (m, 6H), 1.93–2.13 (m, 4H), 7.12 (d, 1H,J=8 Hz), 7.49 (dd, 1H, J=8, 2 Hz), 7.66 (d, 1H, J=2 Hz), 8.15 (t, 1H,J=2 Hz), 8.39 (s, 1H, br), 8.89 (d, 1H, J=2 Hz), 9.06 (d, 1H, J=2 Hz);MS ((+)-ESI) m/z 304 (M+H)⁺; Anal. C₁₉H₁₇N₃O CHN.

The title compound was prepared from3-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)pyridinecarbonitrile (100 mg) and Lawesson's reagent (120 mg) in toluene (10 ml)at reflux, according to General Procedure A, to afford the titlecompound (0.004 g) as a yellow solid: mp. 237–238° C.; ¹H NMR (CDCl₃) δ9.56 (br s, 1H), 9.03 (d, 1H, J=1.9 Hz), 8.87 (d, 1H, J=1.4 Hz), 8.12(s, 1H), 7.87 (s, 1H), 7.50 (d, 1H, J=8.1 Hz), 7.17 (d, 1H, J=8.1 Hz),2.19–1.85 (m, 7H) and 1.59–1.54 (m, 3H); MS ((−)-APCI) m/z 318 [M−H]⁻.

EXAMPLE 225-(3,4-DIFLUOROPHENYL)SPIRO[CYCLOHEXANE-1,3-[3H]INDOLE]-2(1H)-THIONE

5′-(3,5-Difluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one:Prepared according to the procedure for Example 5: mp 180–183° C.;¹H-NMR (CDCl₃) δ 8.35 (s, 1H), 7.59 (d, 1H, J=2.0 Hz), 7.40 (dd, 1H,J=6.2, 2.0 Hz), 7.10–7.03 (m, 2H), 6.99 (d, 1H, J=8.1 Hz), 7.76 (tt, 1H,J=4.3, 2.3 Hz), 2.05–1.62 (m, 10H); MS ((+)APCI) m/z 314 [M+H]⁺.

The title compound was prepared from5′-(3,5-difluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one(100 mg) and Lawesson's reagent (120 mg) in toluene (10 ml) at reflux,according to General Procedure A, to afford the product (0.020 g) as ayellow solid: mp. 232–233° C.; ¹H NMR (CDCl₃) δ 10.05 (br s, 1H), 7.83(s, 1H), 7.44 (dd, 1H, J=8.1 and 1.4 Hz), 7.38–7.30 (m, 1H), 7.26–7.19(m, 3H), 7.11 (d, 1H, J=8.1 Hz), 2.17–1.82 (m, 7H) and 1.66–1.53 (m,3H); MS ((−)-APCI) m/z 328 [M−H]⁻.

EXAMPLE 235-(5-CHLORO-2-THIENYL)SPIRO[CYCLOHEXANE-1,3-[3H]INDOLE]-2(1H)-THIONE

5-(5-Chloro-2-thienyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one:Prepared according to the procedure for Example 5: m.p. 191–192° C., ¹HNMR (CDCl₃) δ 1.6–2.1 (m, 10H), 6.85–6.95 (m, 2H), 6.98 (d, J=4.0 Hz,1H), 7.36 (dd, J=7.5, 1.6 Hz, 1H), 7.53 (d, J=0.9 Hz, 1H), 7.80 (br s,1H); ¹³C-NMR (THF-d₈) δ 21.35, 25.33, 33.12 (t), 48.32 (s), 110.40,121.66, 121.96, 125.44, 127.25 (d), 128.17, 128.43, 136.92, 140.20,143.43, 183.72 (s); MS (EI) m/z 318 (M(+)H)⁺; Anal. (C₁₇H₁₆ClNOS) C, H,N.

The title compound was prepared from5-(5-Chloro-2-thienyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one (100mg) and Lawesson's reagent (120 mg) in toluene (10 ml) at reflux,according to General Procedure A, to afford the product (0.041 g) as ayellow solid: mp. 231–232° C.; ¹H NMR (CDCl₃) δ 9.75 (br s, 1H), 7.82(d, 1H, J=1.2 Hz), 7.43 (dd, 1H, J=8.1 and 1.6 Hz), 7.04–7.02 (m, 2H),6.89 (d, 1H, J=3.8 Hz), 2.15–1.84 (m, 7H) and 1.59–1.52 (m, 3H); MS((−)-APCI) m/z 332/334 [M−H]⁻.

EXAMPLE 245-(1,2-DIHYDRO-2-THIOXOSPIRO[CYCLOHEXANE-1,3-[3H]INDOL]-5-YL)-3-FURANCARBONITRILE

5-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-3-furancarbonitrile:

Prepared according to the procedure for Example 5: m.p. 243–245° C.¹H-NMR (DMSO-d₆) δ 10.48 (s, 1H), 8.62 (d, 1H, J=0.7 Hz), 7.76 (d, 1H,J=1.5 Hz), 7.58–7.55 (dd, 1H), 7.33 (d, 1H, J=0.7 Hz), 6.92–6.90 (d, 1H,J=8.1 Hz), 1.87–1.83 (m, 2H), 1.73–1.53 (m, 8H). MS ((+)EI) m/z 292(M⁺).

The title compound was prepared from5-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-3-furancarbonitrile(100 mg) and Lawesson's reagent (120 mg) in toluene (10 ml) at reflux,according to General Procedure A, to afford the product (0.020 g) as ayellow solid: mp. 264–268° C.; ¹H NMR (CDCl₃) δ 9.66 (br s, 1H), 7.98(s, 2H), 7.59 (dd, 1H, J=8.2 and 1.5 Hz), 7.08 (d, 1H, J=8.2 Hz), 6.78(s, 1H), 2.16–1.85 (m, 7H) and 1.56–1.52 (m, 2H): MS ((−)-APCI) m/z 307[M−H]⁻.

EXAMPLE 255-(3-CHLORO-4-FLUOROPHENYL)SPIRO[CYCLOHEXANE-1,3-[3H]INDOL]-2(1H)-THIONE

5′-(3-Chloro-4-fluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one.Prepared according to the procedure for Example 5: mp 188–189° C.;¹H-NMR (CDCl₃) δ 7.97 (s, 1H), 7.57–7.54 (m, 2H), 7.41–7.34 (m, 2H),7.20 (t, 1H, J=8.7 Hz), 9.96 (d, 1H, J=8.1 Hz), 2.04–1.65 (m, 10H); MS((+)APCI) m/z 330 [M+H]⁺.

The title compound was prepared from5′-(3-Chloro-4-fluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one(100 mg) and Lawesson's reagent (100 mg) in toluene (10 ml) at reflux,according to General Procedure A, to afford the product (0.036 g) as anoff white solid: ¹H NMR (DMSO-d₆) δ 12.74 (br s, 1H), 7.92 (d, 1H, J=1.4Hz), 7.87 (dd, 1H, J=7.1 and 2.3 Hz), 7.70–7.65 (m, 1H), 7.61 (dd, 1H,J=7.1 and 1.5 Hz), 7.49 (t, 1H, J=8.9 Hz), 7.14 (d, 1H, J=8.1 Hz),1.99–1.82 (m, 7H) and 1.40–1.37 (m, 3H): MS ((−)-APCI) m/z 344/346[M−H]⁻.

EXAMPLE 265-(3-CHLORO-5-FLUOROPHENYL)SPIRO[CYCLOHEXANE-1,3-[3H]INDOL]-2(1H)-THIONE

5′-(3-Chloro-5-fluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one

Prepared according to the procedure for Example 5: mp 178–180° C.;¹H-NMR (CDCl₃) δ 8.50 (s, 1H), 7.57 (d, 1H, J=1.8 Hz), 7.39 (dd, 1H,J=6.2, 1.9 Hz), 7.33–7.32 (m, 1 H), 7.15 (dq, 1H, J=5.7, 1.7, 0.7 Hz),7.06 (dq, 1 H, J=4.2, 1.9, 0.4 Hz), 7.00 (d, 1H, J=8.1 Hz), 2.05–1.64(m, 10H); MS ((−)ESI) [M−H]⁻ @ m/z 328.

The title compound was prepared from5′-(3-chloro-5-fluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one(100 mg) and Lawesson's reagent (100 mg) in toluene (10 ml) at reflux,according to General Procedure A, to afford the product (0.039 g) as anoff white solid: ¹H NMR (DMSO-d₆) δ 12.76 (br s, 1H), 7.97 (d, 1H, J=1.1Hz), 7.67 (dd, 1H, J=8.1 and 1.4 Hz), 7.60–7.54 (m, 2H), 7.40 (dt, 1H,J=8.65 and 2.0 Hz), 7.14 (d, 1H, J=8.1 Hz), 1.99–1.83 (m, 7H) and1.41–1.38 (m, 3H): MS ((−)-APCI) m/z 344/346 [M−H]⁻.

EXAMPLE 275-(3,5-DIFLUOROPHENYL)SPIRO[CYCLOHEXANE-1,3-[3H]INDOLE]-2(1H)-THIONE

5′-(3,5-Difluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one

Prepared according to the procedure for Example 5: mp 180–183° C.;¹H-NMR (CDCl₃) δ 8.35 (s, 1H), 7.59 (d, 1H, J=2.0 Hz), 7.40 (dd, 1H,J=6.2, 2.0 Hz), 7.10–7.03 (m, 2H), 6.99 (d, 1H, J=8.1 Hz), 7.76 (tt, 1H,J=4.3, 2.3 Hz), 2.05–1.62 (m, 10H); MS ((+)APCI) m/z 314 [M+H]⁺.

The title compound was prepared from5′-(3,5-difluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one(100 mg) and Lawesson's reagent (100 mg) in toluene (10 ml) at reflux,according to General Procedure A, to afford the title compound 0.029 gas an off white solid: ¹H NMR (DMSO-d₆) δ 12.76 (br s, 1H), 7.84 (s,1H), 7.64–7.56 (m, 1H), 7.46 (d, 1H, J=8.1 Hz), 7.40–7.32 (m, 1H),7.22–7.15 (m, 2H), 1.99–1.80 (m, 7H) and 1.38–1.35 (m, 3H); MS((−)-APCI) m/z 328 [M−H]⁻.

EXAMPLE 285-(1,2-DIHYDRO-2-THIOXOSPIRO[CYCLOHEXANE-1,3-[3H]INDOL]-5-YL)-4-PROPYL-2-THIOPHENECARBONITRILE

5-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-4-propyl-2-thiophenecarbonitrile.The title compound was prepared in a manner similar to Example 5 from5-bromo-4-n-propyl thiophene-2-carbonitrile (1.17 g, 5 mmol),(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol)-5-boronic acid (1.24g, 5 mmol), tetrakis(triphenylphosphine)palladium, potassium carbonate(2.75 g, 21 mmol), water (10 mL), and dimethoxyethane (50 mL) heated atreflux over night, to afford the product (0.7 g, 40%): m.p. 168–171° C.;¹H NMR (DMSO-d₆) δ 10.56 (s, 1H), 7.93 (s, 1H), 7.52–7.51 (d, 1H, J=1.5Hz), 7.33–7.29 (dd, 1H, J=1.6 Hz), 7.00–6.96 (d, 1H, J=8.0 Hz),2.62–2.57 (t, 2H), 1.86 (m, 2H), 1.70–1.56 (m, 11 H), 0.88–0.84 (t, H);MS m/z (APCI (+)) 351 [M+H]⁺. IR (KBr) 1620, 1700, 2200 cm⁻¹. Anal.calc. for C₂₁H₂₂N₂OS.½H₂O C, 70.2; H, 6.39; N, 7.79. Observed. C, 70.67;H, 6.34; N, 7.62.

The title compound was prepared from5-(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-4-propyl-2-thiophenecarbonitrile(90 mg) and Lawesson's reagent (90 mg) in toluene (10 ml) at reflux,according to General Procedure A, to afford the title compound (0.037 g)as an orange solid: ¹H NMR (DMSO-d₆) δ 12.83 (br s, 1H), 7.96 (s, 1H),7.77 (s, 1H), 7.44 (d, 1H, J=7.7 Hz), 7.19 (d, 1H, J=8.0 Hz), 2.60 (t,2H, J=8.0 Hz), 1.98–1.79 (m, 7H), 1.64–1.56 (m, 2H), 1.39–1.35 (m, 2H)and 0.87 (t, 3H, J=7.3 Hz):MS ((−)-APCI) m/z 365 [M−H]⁻.

EXAMPLE 295-(3-FLUORO-4-NITROPHENYL)SPIRO[CYCLOHEXANE-1,3-[3H]INDOL]-2(1H)-THIONE

5-(3-Fluoro-4-nitrophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one:Prepared from(2′-oxo-2,3-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)boronic acid(3.2 g, 12.5 mmol) and 4-bromo-2-fluoro-nitrobenzene (3 g, 13.6 mmol) asdescribed for example 5, to afford the title compound (0.7 g, 16%) as ayellow solid: mp. 213–215° C.; ¹H NMR (DMSO-d₆) δ 1.5–1.8 (m, 8H),1.8–2.0 (m, 2H), 6.96 (d, 1H, J=8.13 Hz), 7.68 (dd, 1H, J=8.13, 1.76Hz), 7.74 (dd, 1 H, J=8.68, 1.76 Hz), 7.86 (d, 1H, J=1.98 Hz), 7.92 (dd,1H, J=13.4, 1.76 Hz), 8.18 (t, 1H, J=8.46 Hz) and 10.52 (s, 1H); MS (EI)m/z=340 (M⁺).

The title compound was prepared from5-(3-fluoro-4-nitrophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one (90mg) and Lawesson's reagent (90 mg) in toluene (10 ml) at reflux,according to General Procedure A, to afford the product (0.021 g) as ayellow solid: ¹H NMR (DMSO-d₆) δ 12.82 (br s, 1H), 8.21 (t, 1H, J=8.4Hz), 8.07 (d, 1H, J=1 Hz), 7.98 (dd, 1H, J=13.1 Hz), 7.79 (dt, 1H, J=8.1and 2.6 Hz), 7.19 (1H, J=8.2 Hz), 1.99–1.83 (m, 7H) and 1.42–1.39 (m,3H): MS ((−)-APCI) m/z 355 [M−H]⁻.

EXAMPLE 304-(1,2-DIHYDRO-2-THIOXOSPIRO[CYCLOHEXANE-1,3-[3H]INDOL]-5-YL)-2-FURANCARBONITRILE

4-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-2-furancarbonitrile:A solution of 3-bromo-5-cyano-furan (0.75 g, 4.4 mmol), andtetrakis(triphenylphosphine)palladium(0) (0.4 g) in ethylene glycoldimethyl ether (20 cm³) was stirred under N₂ for 20 minutes. To thismixture was then added(spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid (1.6 g,6.5 mmol) and sodium acetate (1.4 g, 13.1 mmol) in water (5 cm³). Thesolution was brought to reflux for 18 hours and then cooled to roomtemperature, poured into 2N NaOH and extracted with EtOAc (×3). Thecombined extracts were washed with water, brine, dried (MgSO₄), andevaporated. The residue was purified by column chromatography (SiO₂,EtOAc, hexane) to afford the product (0.45 g, 36%) as an off-whitesolid. mp: 240–242° C.; ¹H NMR (DMSO-d₆) δ 10.4 (s, 1H), 8.5 (s, 1H),8.2 (s, 1H), 7.7 (s, 1H), 7.5 (dd, 1H, J=1.56.5 Hz), 6.9 (d, 1H, J=8.0Hz), 2.0–1.6 (m, 10H); MS (EI) M⁺ @ m/z 292.

The title compound was prepared from4-(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-2-furancarbonitrile(67 mg) and Lawesson's reagent (67 mg) in toluene (10 ml) at reflux,according to General Procedure A, to afford the title compound (0.018 g)as a yellow solid: ¹H NMR (DMSO-d₆) δ 12.74 (s, 1H), 8.68 (s, 1H), 8.26(s, 1H), 7.96 (s, 1H), 7.62 (dd, 1H, J=8.0 and 1.0 Hz), 7.10 (s, 1H,J=8.1 Hz), 1.94–1.78 (m, 7H) and 1.35–1.32 (m, 3H): MS ((−)-APCI) m/z307 [M−H]⁻.

EXAMPLE 315″-(3-CHLOROPHENYL)SPIRO[CYCLOBUTANE-1,3″-[3H]INDOL]-2″(1″H)-THIONE

5-Bromospiro[cyclobutane-1,3-[3H]indol]-2(1H)-one: To a stirred solutionof spiro[cyclobutane-1,3′-[3H]indol]-2′(1′H)-one (J. Med. Chem. 1987,824–9) (1.0 g, 6 mmol) in glacial acetic acid (10 mL) was added dropwiseat room temperature a solution of bromine (0.30 mL, 6 mmol) in glacialacetic acid (6 mL). After stirring for 10 min, anhydrous sodium acetate(0.47 g, 6 mmol) was added and the solution was concentrated in vacuo.The residue was dissolved in ethyl ether (50 μL) and washed sequentiallywith water (50 mL), aqueous saturated sodium bicarbonate solution (50mL), water (50 mL) and brine (30 mL). The organic layer was dried overmagnesium sulfate, filtered and concentrated in vacuo. Crystallizationfrom ethyl ether yielded the product as a white fluffy solid (1.1 g,73%), mp 235–7° C. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.15–2.41 (m, 6 H), 6.74(d, 1 H, J=8.2 Hz), 7.33 (dd, 1 H, J=2, 8.2 Hz), 7.75 (d, 1 H, J=2 Hz),10.36 (bs, 1 H). MS (EI) m/z 251 [M⁺]. Anal. Calcd for C₁₁H₁₀BrNO: C,52.41; H, 4.00; N, 5.56. Found: C, 51.98; H, 4.24; N, 5.42.

To a solution of 5-bromospiro[cyclobutane-1,3-[3H]indol]-2(1H)-one (0.6g, 2 mmol) in ethylene glycol dimethyl ether (50 mL) under a nitrogenatmosphere was added tetrakis(triphenylphosphine)palladium(0) (140 mg,0.1 mmol). To the solution was added sequentially 3-chlorophenyl boronicacid (0.48 g, 3 mmol) and potassium carbonate (0.76 g, 5 mmol) in water(5 mL). The mixture was heated to 80° C. for 3 h and allowed to cool.The reaction mixture was poured into water (100 mL) and extracted withethyl acetate (3×100 mL). The organic layers were combined, washed withbrine (50 mL) and dried over magnesium sulfate. The solution wasfiltered, concentrated in vacuo, and the residue was purified by HPLC(Zorbax PRO, C18, 10u, 15A, 50×250 mm; 35% Water/65% AcCN; 254 NM; AMB.temp.) to give5-(3-chlorophenyl)spiro[cyclobutane-1,3-[3H]indole]-2(1H)-one (200 mg,35%) as a white powder, mp 199.5–201° C. ¹H NMR (DMSO-d₆, 300 MHz) δ2.21–2.28 (m, 2 H), 2.40–2.45 (m, 4 H), 6.87 (d, 1 H, J=8.1 Hz), 7.37(‘d’, 1 H), 7.44–7.52 (m, 2 H), 7.65 (bd, 1 H, J=7.8 Hz), 7.76 (bs, 1H), 7.92 (bs, 1 H), 10.35 (s, 1 H). MS (EI) m/z 283 [M⁺]. Anal. Calcdfor C₁₇H₁₄ClNO: C, 71.96; H, 4.97; N, 4.94. Found: C, 70.75; H, 5.07; N,4.68.

The title compound was prepared from5-(3-Chlorophenyl)spiro[cyclobutane-1,3-[3H]indole]-2(1H)-one (55 mg)and Lawesson's reagent (55 mg) in toluene (10 ml) at reflux, accordingto General Procedure A, to afford the title compound 0.016 g as anorange solid: ¹H NMR (DMSO-d₆) δ 12.58 (br s, 1H), 8.07 (d, 1H, J=1.5Hz), 7.82 (t, 1H, J=1.7 Hz), 7.70 (d, 1H, J=7.74 Hz), 7.60 (dd, 1H,J=8.12 and 1.71 Hz), 7.49 (t, 1H, J=7.9 Hz), 7.41 (d, 1H, J=8.32 Hz),7.05 (d, 1H, J=8.14 Hz) and 2.57–2.27 (m, 6H); MS ((−)-APCI) m/z 298/300[M−H]⁻.

EXAMPLE 325″-(2-CHLOROPHENYL)SPIRO[CYCLOHEXANE-1,3″-[3H]INDOL]-2″(1″H)-THIONE

The title compound was prepared from5″-(2-Chlorophenyl)spiro[cyclohexane-1,3″-[3H]indole]-2″(1″H)-thione (90mg) and Lawesson's reagent (90 mg) in toluene (10 ml) at reflux,according to General Procedure A, to afford the product 0.042 g as anoff white solid: ¹H NMR (DMSO-d₆) δ 12.75 (br s, 1H), 7.80 (d, 1H, J=1.1Hz), 7.58–7.55 (m, 1H), 7.48–7.36 (m, 4H), 7.16 (d, 1H, J=8.0 Hz); MS((−)-APCI) m/z 326/328 [M−H]⁻.

EXAMPLE 335″-(4-CHLOROPHENYL)SPIRO[CYCLOHEXANE-1,3″-[3H]INDOLE]-2″(1″H)-THIONE

The title compound was prepared from5-(4-chlorophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one (90 mg) andLawesson's reagent (90 mg) in toluene (10 ml) at reflux, according toGeneral Procedure A, to afford the product 0.035 g as an off whitesolid: ¹H NMR (DMSO-d₆) δ 12.74 (br s, 1H), 7.91 (d, 1H, J=1.3 Hz), 7.69(d, 2H, J=5.5 Hz), 7.60 (dd, 1H, J=8.1 and 1.4 Hz), 7.50 (d, 2H, J=8.5Hz), 7.15 (d, 1H, J=8.1 Hz), 1.99–1.83 (m, 7H) and 1.50–1.36 (m, 3H); MS((−)-APCI) m/z 326/328 [M−H]⁻.

EXAMPLE 345-(1″,2″-DIHYDRO-2″-THIOXOSPIRO[CYCLOHEXANE-1,3″-[3H]INDOL]-5″-YL)-4-METHYL-2-THIOPHENECARBONITRILE

5-Bromo-4-methyl-2-thiophene carboxaldehyde: To a solution ofdiethylamine (28 g, 0.383 mol) in anhydrous THF (400 mL) was added at−40° C. under nitrogen a solution of n-BuLi (2.5 M, 153 mL, 0.383 mol)in hexane. After addition, the solution was stirred at −40° C. undernitrogen for 30 minutes, cooled to −78° C. and treated dropwise with asolution of 2-bromo-3-methylthiophene (45 g, 0.254 mol) in anhydrous THF(450 mL). The reaction solution was stirred at −78° C. for 30 minutesand treated with anhydrous DMF (100 mL). The mixture was allowed to warmto ambient temperature and was quenched with 1N aqueous hydrochloridesolution (1 L). The solution was extracted with ethyl acetate (3×450 mL)and the extracts washed with water, brine and dried (MgSO₄). Afterremoval of solvent in vacuo, the title compound was obtained as a whitesolid (46 g, 88.3%). A sample of the product was crystallized fromhexane: mp 63–65° C.; IR (KBr) 1654 cm⁻¹. ¹H-NMR (CDCl₃) δ 9.75 (s, 1H),7.45 (s, 1H), 2.26 (s, 3H); MS (EI) m/z 204/206 (M+). Anal. Calc. ForC₆H₅BrOS: C, 35.14; H, 2.46. Found: C, 35.00; H, 2.44.

5-Bromo-4-methyl-2-thiophenecarbonitrile: Prepared from5-bromo-4-methyl-2-thiophene carboxaldehyde using the procedure ofExample 5. White solid: mp 40–42° C.; IR (KBr) 2200 cm⁻¹; ¹H-NMR (CDCl₃)δ 7.29 (s, 1H), 2.21 (s, 3H). MS (EI) m/z 201/203 (M⁺, 98%/100%); Anal.Calc. For C₆H₄BrNS: C, 35.66; H, 1.99; N, 6.93. Found: C, 36.00; H,2.14; N, 6.76.

Prepared according to the procedure for Example 5 using(2′-oxo-[2,3-dihydro-3,3-dimethyl-1,3′-[3H]indol]-5′-yl)boronic acid(357 mg, 1.7 mmol) and 5-bromo-4-methylthiophene-2-carbonitrile (295 mg,1.5 mmol) to afford5-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-4-methylthiophene-2-carbonitrile (227 mg, 0.8 mmol, 55%) as a white solid: mp.192.3–193° C., ¹H NMR (DMSO-d₆) δ 1.29 (s, 6H), 2.29 (s, 3H), 6.97 (d,J=8.0 Hz, 1H), 7.34 (dd, J=8.0, 1.8 Hz, 1H), 7.49 (d, J=1.7 Hz, 1H),7.84 (s, 1H), 10.57 (s, 1H); MS (EI) m/z 282 (M)⁺; Anal. C₁₆H₁₄N₂OS.

The title compound was prepared from5-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-4-methylthiophene-2-carbonitrile (0.77 g, 2.39 mmol) and phosphorouspentasulfide (0.42 g, 0.96 mmol) in toluene (20 ml) at reflux. After 3h, the reaction was cooled and partitioned between water and EtOAc, theorganic layer was separated, dried (MgSO₄) and evaporated. The residuewas purified by column chromatography (SiO₂, EtOAc-hexane gradientelution) to afford the product (0.25 g, 0.73 mmol, 30%) as an orangesolid: ¹H NMR (DMSO-d₆) δ 12.82 (br s, 1H), 7.88 (s, 1H), 7.82 (d, 1H,J=2 Hz), 7.49 (dd, 1H, J=8.1, 1.6 Hz), 7.18 (d, 1H, J=8.1 Hz), 1.99–1.80(m, 7H) and 1.40–1.36 (m, 3H); MS ((−)-APCI) m/z 321 [M−H]⁻.

EXAMPLE 355-(1″,2″-DIHYDRO-2″-THIOXOSPIRO[CYCLOHEXANE-1,3″-[3H]INDOL]-5″-YL)-2-THIOPHENECARBONITRILE

5-Bromo-2-thiophenecarbonitrile: A mixture of 5-bromo-2-thiophenecarboxaldehyde (96.0 g, 500 mmol), hydroxylamine hydrochloride (111.9 g,500 mmol), pyridine (500 mL), and ethanol (500 mL) was heated undernitrogen at reflux for two hours. The reaction mixture was cooled toambient temperature and concentrated in vacuo to give an oil. The crudeproduct was triturated twice with ice water and the solid obtained wascollected on a filter. A mixture of a portion of the above solid (44.31g, 215 mmol), copper (II) acetate monohydrate (4.2 g, 21 mmol) inacetonitrile (1.4 L) was heated at reflux for three hours. The solventwas removed in vacuo and the residue was dissolved in ethyl acetate. Thesolution was washed with 5% aqueous sulfuric acid (2×30 mL), water (2×30mL), brine (20 mL), and dried (MgSO₄). The solvent was removed in vacuoand the residue was dissolved in a minimum amount of chloroform (1 L)and allowed to crystallize. The crystals obtained were collected on afilter and the filtrate was concentrated and purified by achromatography (silica gel, chloroform) to give the subtitled compoundas an off-white solid (31.5 g combined, 58%). IR (film) 2200 cm⁻¹.¹H-NMR (CDCl₃) δ 7.39–7.38 (d, 1H, J=4.1 Hz), 7.10 (d, 1H, J=4.0 Hz); MS(EI) m/z 187 (M(+), 98%) 189 (M⁺, 100%).

5-(2′-Oxo-2′,3′-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′yl-2-thiophenecarbonitrilewas prepared according to the procedure for Example 5 using5-bromo-2-thiophenecarbonitrile and(2′-oxo-2′,3′-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)boronicacid: mp. 225–228° C.; ¹H NMR (DMSO-d₆) δ 1.63 (m, 8H), 1.90 (m, 2H),6.91 (d, 1H, J=8.13 Hz), 7.55 (dd, 1H, J=8.13, 1.76 Hz), 7.60 (d, 1H,J=4.17 Hz), 7.75 (d, 1H, J=1.76 Hz), 7.93 (d, 1H, J=4.17 Hz), 10.51 (s,1H); MS ((+)APC1) m/z 309 [M+H]⁺.

The title compound was prepared from5-(2′-oxo-2′,3′-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′yl-2-thiophenecarbonitrile(0.69 g) and phosphorous pentasulfide (0.4 g) in toluene (20 ml) atreflux. After 3 h. the reaction was cooled, poured into sat. aqueoussodium hydrogen carbonate solution, and extracted with EtOAc. Theorganic layer was separated, dried (MgSO₄) and evaporated. The residuewas purified by column chromatography (SiO₂, EtOAc-hexane gradientelution) to afford the title compound (0.215 g) as an orange solid: ¹HNMR (DMSO-d₆) δ 12.82 (br s, 1H), 8.00–7.98 (m, 2H), 7.74 (d, 1H, J=4.1Hz), 7.69 (dd, 1H, J=8.2 and 1.6 Hz), 7.14 (d, 1H, J=8.1 Hz), 1.99–1.83(m, 7H) and 1.40–1.37 (m, 3H); MS ((−)-APCI) m/z 323 [M−H]⁻.

EXAMPLE 365″-(3-FLUOROPHENYL)SPIRO[CYCLOHEXANE-1,3″-[3H]INDOL]-2″(1″H)-THIONE

5′-(3-Fluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one:Prepared according to the procedure for Example 5: mp 171–172° C.;¹H-NMR (CDCl₃) δ 8.43 (s, 1H), 7.62 (d, 1H, J=1.8 Hz), 7.42 (dt, 1H,J=6.2, 2.0 Hz), 7.39–7.37 (m, 1 H), 7.33 (dt, 1H, J=5.1, 1.3 Hz), 7.26(dq, 1 H, J=5.9, 2.1 Hz), 7.05–6.99 (m, 2H), 2.03–1.64 (m, 10H); MS((+)APCI) m/z 296 [M+H]⁺.

The title compound was prepared from5′-(3-fluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one (0.70g) and phosphorous pentasulfide (0.4 g) in toluene (20 ml) at reflux.After 3 h. the reaction was cooled, poured into sat. aqueous sodiumhydrogen carbonate solution, and extracted with EtOAc, the organic layerwas separated, dried (MgSO₄) and evaporated. The residue was purified bycolumn chromatography (SiO₂, EtOAc-hexane gradient elution) to affordthe product (0.42 g) as an off white solid: ¹H NMR (DMSO-d₆) δ 12.75 (brs, 1H), 7.95 (d, 1H, J=1.5 Hz), 7.64 (dd, 1H, J=8.13 and 1.5 Hz),7.53–7.48 (m, 3H), 7.21–7.14 (m, 2H), 1.99–1.83 (m, 7H) and 1.40–1.37(m, 3H); MS ((−)-APCI) m/z 310 [M−H]⁻.

EXAMPLE 375-(3-HYDROXYPHENYL)SPIRO[CYCLOHEXANE-1,3-[3H]INDOL]-2(1H)-THIONE

5′-(3-Hydroxyphenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one:Prepared according to the procedure for example 5: mp. 213–216° C.; ¹HNMR (CDCl₃) δ 1.60–1.96 (m, 10H), 6.78–6.82 (m, 1H), 6.94 (d, 1H, J=8Hz), 7.01–7.04 (m, 2H), 7.23 (t, 1H, J=7.7 Hz), 7.38 (d, 1H, J=8 Hz),7.61 (s, 1H), 8.91 (s, 1H) and 9.73 (s, 1H, br); MS ((+)-APCI) m/z 294[M+H]⁺.

The title compound was prepared from5′-(3-hydroxyphenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one (100mg) and Lawesson's reagent (110 mg) in toluene (10 ml) at reflux,according to General Procedure A, to afford the title compound (0.0045g) as an off white solid: ¹H NMR (CDCl₃) δ 9.59 (br s, 1H), 7.89 (s,1H), 7.49 (dd, 1H, J=8.1 and 1.5 Hz), 7.33 (t, 1H, J=7.9 Hz), 7.15–7.10(m, 3H), 6.84 (dd, 1H, J=8.0 and 2.2 Hz), 2.17–2.05 (m, 2H), 1.98–1.88(m, 5H) and 1.57–1.53 (m, 3H): MS ((−)-APCI) m/z 308 [M−H]⁻.

EXAMPLE 38 5-(3-CHLOROPHENYL)-3,3-DIETHYL-1,3-DIHYDRO-2H-INDOLE-2-THIONE

A solution of oxindole (40 g, 0.3 mol) in dry THF (400 ml) under N₂ wascooled to −25° C. and treated drop wise with n-butyl lithium (2.5M inhexanes, 240 ml, 0.6 mol). To the resulting solution was addedN,N,N′,N′-tetramethylethylenediamine (90.4 ml, 0.6 mol). After 30 min.iodoethane (48 ml, 0.6 mol) was added and the reaction mixture wasallowed to warm to room temperature and stirred over night. The reactionmixture was poured into aqueous NH₄Cl solution, extracted with EtOAc(2×) and the combined organic layers were washed with dil. HCl, water,brine, dried (MgSO₄) and concentrated. The residual oil was trituratedwith hexane to afford the crude product (24.5 g, 51%). A sample (3 g)was recrystallized from EtOAc/hexane to obtain 3-ethyl-indol-2-one (1.4g), m.p. 100–101° C.; ¹H-NMR (DMSO-d₆) δ 0.76 (t, 3H, J=7.5 Hz), 1.8–2.0(m, 2H), 3.38 (t, 3H, J=5.7 Hz), 6.8 (dt, 1H, J=7.69, 0.45 Hz), 6.93(dt, 1H, J=7.45, 1.10 Hz), 7.15 (m, 1H), 7.22 (m, 1H), 10.3 (s, 1H); MS(ESI) m/z 270 [M+H].

A solution of 3-ethyl-indol-2-one (16 g, 0.1 mol) in dry THF (200 ml)under N₂ was cooled to −25° C. and treated drop wise with n-butyllithium(2.5M in hexanes, 80 ml, 0.2 mol). To the resulting solution was addedN,N,N′,N′-tetramethylethylenediamine (30 ml, 0.2 mol). After 30 min.iodoethane (8 ml, 0.1 mol) was added and the reaction mixture wasallowed to warm to RT and stirred over night. The reaction mixture waspoured into an aqueous NH₄Cl solution, extracted with EtOAc (2×) and thecombined organic layers were washed with dil. HCl, water, brine, dried(MgSO₄) and concentrated. The residual oil was triturated with hexane toafford 3,3-diethylindol-2-one (9 g, 45%), m.p. 156–159° C.; ¹H NMR(DMSO-d₆) δ 10.44 (s, 1H), 7.70–7.69 (t, 1H), 7.62–7.59 (m, 1H), 7.58(d, 1H J=1.7 Hz), 7.53–7.50 (m, 1H), 7.45–7.41 (t, 1H), 7.36–7.35 (m,1H), 7.34–7.33 (m, 1H), 6.91–6.89 (d, 1H J=8.2 Hz), 1.87–1.80 (m, 2H),1.77–1.70 (m, 2H), 0.54–0.50 (t, 6H); MS/ (+ESI) m/z 190 (M+H).

A solution of 3,3-diethylindol-2-one (8 g, 40 mmol) and sodium acetate(4 g, 48 mmol) in acetic acid (100 ml) was treated with bromine (6.4 g,40 mmol). After 30 min. the mixture was diluted with water and extractedwith EtOAc (2×); the combined organic layers were washed with water,sat. sodium hydrogen carbonate solution, then brine, dried (MgSO₄) andevaporated to afford the crude product (7.6 g, 75%). A sample wasrecrystallized from EtOAc/hexane to obtain5-bromo-1,3-dihydro-3,3-diethyl-[2H]-indol-2-one, m.p. 164–165° C.;¹H-NMR (DMSO-d₆) δ 10.45 (s, 1H), 7.41–7.40 (d, 1H, J=2.2 Hz), 7.34–7.31(m, 1H), 6.78–6.76 (d, 1H, J=8.2 Hz), 1.78–1.65 (m, 4H), 0.50–0.46 (m,6H); MS (−ESI) m/z 266/268 (M−H).

A solution of 5-bromo-1,3-dihydro-3,3-diethyl-[2H]-indol-2-one (2.7 g,10 mmol), 3-chlorophenylboronic acid (1.6 g, 10 mmol), potassiumcarbonate (4 g, 30 mmol) and tetrakis(triphenylphosphine)palladium(0)(0.5 g, 0.4 mmol) in dimethoxyethane (100 ml), ethanol (25 ml), andwater (25 ml) was heated to reflux for 6 hours. After cooling to roomtemperature, the mixture was diluted with water and extracted with EtOAc(2×). The combined organic extracts were washed with water, then brine,dried (MgSO₄) and evaporated. The residue was purified by columnchromatography (SiO₂, EtOAc:hexane 1:3) to afford5-(3-chloro-phenyl)-3,3-diethyl-1,3-dihydro-indol-2-one compound (0.8 g,27%), m.p. 195–197° C.; ¹H-NMR (DMSO-d₆) δ 7.70 (t, 1H, J=2 Hz),7.62–7.60 (m, 1H), 7.58 (d, 1H, J=1.7 Hz), 7.52 (dd, 1H, J=8.1, 2 Hz),7.43 (t, 1H, J=7.9 Hz), 7.36–7.33 (m, 1H), 6.90 (d, 1H, J=8.1 Hz),1.87–1.70 (m, 4H) and 0.52 (t, 6H, J=7.4 Hz); MS (+)APCI) m/z 300/302(M−H).

The title compound was prepared from5-(3-chloro-phenyl)-3,3-diethyl-1,3-dihydro-indol-2-one compound (100mg) and Lawesson's reagent (100 mg) in toluene (10 ml) at reflux,according to General Procedure A, to afford the product (0.023 g) as ayellow solid: ¹H NMR (DMSO-d₆) δ 12.73 (br s, 1H), 7.77 (t, 1H, J=1.8Hz), 7.75 (d, 1H, J=1.6 Hz), 7.68–7.62 (m, 2H), 7.48 (t, 1H, J=7.9 Hz),7.40 (d, 1H, J=8.3 Hz), 7.09 (d, 1H, J=8.1 Hz), 2.07–2.00 (m, 2H),1.86–1.79 (m, 2H) and 0.37 (t, 6H, J=7.3 Hz): MS ((−)-APCI) m/z 314/316[M−H]⁻.

EXAMPLE 395-[4-FLUORO-3-(TRIFLUOROMETHYL)PHENYL]SPIRO[CYCLOHEXANE-1,3-[3H]INDOL]-2(1H)-THIONE

5-[4-Fluoro-3-(trifluoromethyl)phenyl]spiro[cyclohexane-1,3-[3H]indol]-2(1H)-onewas prepared from(2′-oxo-2,3-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)boronic acid(2.5 g, 10 mmol) and 5-bromo-2-fluoro-trifluoromethylbenzene (2 g, 8mmol) as described for Example 5, to afford the title compound (0.87 g,30%) as a solid: mp. 222° C.; ¹H NMR (DMSO-d₆) δ 1.5–1.8 (m, 8 H),1.8–2.0 (m, 2 H), 6.92 (d, 1 H, J=8.13 Hz), 7.51 (dd, 1 H, J=8.13, 1.76Hz), 7.55 (dd, 1 H, J=10.54, 9.01 Hz), 7.72 (d, 1 H, J=1.76 Hz), 7.90(dd, 1 H, J=7.03, 2.20 Hz), 7.98 (m, 1 H) and 10.39 (s, 1 H); MS (EI)m/z 363 (M⁺).

The title compound was prepared from5-[4-Fluoro-3-(trifluoromethyl)phenyl]spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one(90 mg) and Lawesson's reagent (90 mg) in toluene (10 ml) at reflux,according to General Procedure A, to afford the product (0.016 g) as ayellow solid: ¹H NMR (DMSO-d₆) δ 12.75 (br s, 1H), 8.06–8.00 (m, 1H),7.96–7.92 (m, 2H), 7.66–7.56 (m, 2H), 7.16 (d, 1H, J=8.1 Hz), 1.99–1.83(m, 7H) and 1.41–1.38 (m, 3H): MS ((−)-APCI) m/z 378 [M−H]⁻.

EXAMPLE 404-(1,2-DIHYDRO-2-THIOXOSPIRO[CYCLOHEXANE-1,3-[3H]INDOL]-5-YL)-2-FLUOROBENZONITRILE

The title compound was prepared from4-(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-2-fluorobenzonitrile(90 mg) and Lawesson's reagent (90 mg) in toluene (10 ml) at reflux,according to General Procedure A, to afford the title compound (0.050 g)as an orange solid: ¹H NMR (DMSO-d₆) δ 12.80 (br s, 1H), 8.04 (d, 1H,J=1.3 Hz), 7.98 (t, 1H, J=7.5 Hz), 7.92 (dd, 1H, J=11.3 and 1.3 Hz),7.76 (d, 2H, J=8.0 Hz), 7.18 (d, 1H, J=8.2 Hz), 1.99–1.82 (m, 7H) and1.40–1.38 (m, 3H); MS ((−)-APCI) m/z 335 [M−H]⁻.

EXAMPLE 415-(1,2-DIHYDRO-2-THIOXOSPIRO[CYCLOHEXANE-1,3-[3H]INDOL]-5-YL)4-N-BUTYL-2-THIOPHENECARBONITRILE

The title compound was prepared in a manner similar to Example 5 from5-bromo-4-n-butyl thiophenecarbonitrile (1.24 g, 5.1 mmol),(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol)-5-boronic acid (1.24g, 5.05 mmol), tetrakis(triphenylphosphine)palladium (0.25 g), potassiumcarbonate (2.75 g, 21 mmol), water (10 mL), and dimethoxyethane (50 mL)heated at reflux for 5 hours to afford5-(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)4-n-butyl-2-thiophenecarbonitrile(1 g, 54%), m.p. 130–132° C. ¹H NMR (DMSO-d₆) δ 10.56 (s, 1H), 7.92 (s,1H), 7.52–7.51 (d, 1H, J=1.2 Hz), 7.32–7.29 (dd, 1H, J=1.5 Hz),6.98–6.96 (d, 1H, J=8.0 Hz), 2.64–2.59 (t, 2H), 1.99–1.86 (m, 2H),1.70–1.50 (m, 11H), 1.32–1.22 (m, 2H), 0.86–0.82 (t, 3H); MS (APCI (+))m/z 365 [M+H]⁺; IR (KBr) 1620, 1700, 2200 cm⁻¹; Anal. calc.C₂₂H₂₄N₂OS.¼H₂O. C, 71.61; H, 6.69; N, 7.59. observed C, 71.13; H, 6.61;N, 6.91.

The title compound was prepared from5-(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)4-n-butyl-2-thiophenecarbonitrile (90 mg) and Lawesson's reagent (90 mg)in toluene (10 ml) at reflux, according to General Procedure A, toafford the product (0.050 g) as an orange solid: ¹H NMR (DMSO-d₆) δ12.83 (br s, 1H), 7.95 (s, 1H), 7.77 (s, 1H), 7.44 (d, 1H, J=8.1 Hz),7.18 (d, 1H, J=8.1 Hz), 2.63 (t, 1H, J=8.0 Hz), 1.99–1.77 (m, 7H),1.60–1.50 (m, 2H), 1.39–1.35 (m, 3H), 1.29–1.22 (m, 2H) and 0.81 (t, 3H,J=7.3 Hz): MS ((−)-APCI) m/z 379 [M−H]⁻.

EXAMPLE 425-(3-FLUORO-5-METHOXYPHENYL)SPIRO[CYCLOHEXANE-1,3-[3H]INDOL]-2(1H)-THIONE

The title compound was prepared from5-(3-Fluoro-5-methoxyphenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-one(90 mg) and Lawesson's reagent (90 mg) in toluene (10 ml) at reflux,according to General Procedure A, to afford the product (0.043 g) as anoff-white solid: ¹H NMR (DMSO-d₆) δ 12.74 (br s, 1H), 7.90 (s, 1H), 7.63(dd, 1H, J=8.1 and 1.2 Hz), 7.13 (d, 1H, J=8.1 Hz), 7.08 (d, 1H, J=10Hz), 7.01 (s, 1H), 6.83 (dt, 1H, J=11 and 2.0 Hz), 1.99–1.83 (m, 7H) and1.40–1.37 (m, 3H): MS ((−)-APCI) m/z 340 [M−H]⁻.

EXAMPLE 435-(3-CHLOROPHENYL)-N-HYDROXYSPIRO[CYCLOHEXANE-1,3′-[3H]INDOL]-2-AMINE

To a solution of5′-(3-Chlorophenyl)spiro[cyclohexane-1,3′-[3H]indole]-2′(1′H)-thione(0.74 g, 2.25 mmol) in dry THF (15 ml) was added sodium hydride (60% inoil, 0.1 g, 2.5 mmol) at room temperature. After 15 min., methyl iodide(0.18 ml, 2.88 mmol) was added. After 1 h, the reaction mixture waspartitioned between water and EtOAc, the organic layer was washed withbrine, dried (MgSO₄) and evaporated to give5-(3-chlorophenyl)-2-(methylthio)spiro[cyclohexane-1,3′-[3H]indole](0.80 g, 100%) which was used without further purification:

To a solution of the last cited compound (1.96 g, 5.73 mmol) in DMSO (20ml) was added hydroxylamine (60% in water, 5 ml) and the mixture washeated to 120° C. After 1 h., the reaction was cooled, partitionedbetween diethyl ether and saturated aqueous ammonium chloride solution.The organic layer was washed with water and brine and then dried (MgSO₄)and evaporated. The crude product was then crystallized from MeOH toafford the title compound (1.67 g, 5.08 mmol, 89%) as a white solid: ¹HNMR (CDCl₃) δ 7.52 (t, 1H, J=1.7 Hz), 7.43–7.28 (m, 7H), 6.83 (d, 1H,J=8 Hz) and 1.98–1.51 (m, 10H); MS (ESI (+)) m/z 327/329 [M+H]⁺.

EXAMPLE 44N-(ACETYLOXY)-5′-(3-CHLOROPHENYL)SPIRO[CYCLOHEXANE-1,3′-[3H]INDOL]-2″-AMINE

To a solution of5-(3-Chlorophenyl)-N-hydroxyspiro[cyclohexane-1,3′-[3H]indol]-2-amine(0.23 g, 0.71 mmol) in methylene chloride-methanol (9:1, 10 ml) wasadded acetic anhydride (0.08 ml, 0.8 mmol) and 4-dimethylaminopyridine(catalytic amount) under a nitrogen atmosphere. After 20 min., thereaction was evaporated and the product purified by columnchromatography (SiO₂, methanol:methylene chloride 5:95). The product wasthen triturated with di-iso-propylether to afford the title compound(0.12 g, 0.32 mmol, 45%): ¹H NMR (CDCl₃) δ 7.52–7.51 (m, 2H), 7.43–7.27(m, 5H), 6.88 (d, 1H, J=8 Hz), 2.27 (s, 3H), 2.04–1.92 (m, 4H),1.84–1.74 (m, 4H) and 1.72–1.57 (m, 2H); MS (ESI (+)) m/z 369/371[M+H]⁺; C₂₁H₂₁ClN₂O₂.0.5H₂O requires C, 66.98; H, 5.64; N, 7.34. FoundC, 66.74: H, 5.86: N, 7.41.

EXAMPLE 455′-(3-FLUOROPHENYL)SPIRO[CYCLOHEXANE-1,3′-[3H]INDOL]-2′(1′H)-ONE OXIME

Prepared according to the method for Example 42 from5′-(3-fluorophenyl)spiro[cyclohexane-1,3′-[3H]indole]-2′(1′H)-thione(0.59 g, 1.90 mmol) to afford the title compound (0.053 g, 0.17 mmol,10%): ¹H NMR (DMSO-d₆) δ 9.59 (s, 1H), 9.40 (s, 1H), 7.57 (d, 1H, J=1.5Hz), 7.46–7.39 (m, 4H), 7.11–7.05 (m, 1H), 6.80 (d, 1H, J=8.1 Hz),2.04–1.97 (m, 2H), 1.82–1.74 (m, 2H) and 1.66–1.42 (m, 6H): MS (ESI (−))m/z 309 [M−H]⁻, C₁₉H₁₉FN₂O requires C: 73.53, H: 6.17, N: 9.03. Found C,73.33, H: 6.07, N: 8.83.

EXAMPLE 465′-(2-FLUOROPHENYL)SPIRO[CYCLOHEXANE-1,3′-[3H]INDOL]-2′(1′H)-ONE OXIME

5′-bromospiro{cyclohexane-1,3′-[3H]indol}-2′(1′H)-one 2′(O-benzyloxime).5′-Bromo-2′-(methylthio)spiro[cyclohexane-1,3′-[3H]indole] (9.0 g, 28.98mmol) and O-benzylhydroxylamine hydrochloride (13.8 g, 86.9 mmol) werecombined in methanol (150 mL) and heated to 45° C. for 6 hours. Methanolwas evaporated in vacuo. Ethyl acetate was added to the residue and thismixture was washed with ammonium chloride solution. Ethyl acetate wasdried over magnesium sulfate, ethyl acetate collected evaporated invacuo and the residue was flash chromatographed on alumina 90 (9:1Hexane/EtOAc) to the desired product (6.5 g, 60%). ¹H NMR (DMSO-d₆, 300MHz) δ 1.38–1.70 (m, 8H), 1.92–2.06 (m, 2H), 5.06 (s, 2H), 6.71 (d, 1H,J=8.26 Hz), 7.22–7.43 (m, 7H), 9.62 (s, 1H).

Procedure A

5′-(2-Fluorophenyl)-spiro[cyclohexane-1,3′-[3H]indol]-2′(1H)-one2(O-benzyloxime) 5′-Bromospiro{cyclohexane-1,3′-[3H]indol}-2′(1′H)-one2′(O-benzyloxime) (1.0 g, 2.6 mmol), and tetrakistriphenyl phosphine Pd(0) (0.14 g, 0.12 mmol) were stirred under an atmosphere of nitrogen inethylene glycol dimethyl ether (23 mL). After 15 minutes, 2-flurophenylboronic acid (0.72 mg, 5.2 mmol) was added, followed by sodium carbonate(1.6 g, 15.6 mmol) in water (6.0 mL). The reaction was heated to refluxovernight, cooled to room temperature and filtered through a Celiteplug. Saturated ammonium chloride was added. The water layer wasextracted with ethyl acetate (3×100 mL). The combined organic layerswere dried (MgSO₄), filtered, and the solvent removed in vacuo. Theproduct was purified by flash silica gel chromatography; (eluant: 10:0.5hexane:ethyl acetate) to give the desired target compound (0.75 g, 1.8mmol, 72%) as a viscous oil. ¹H NMR (500 MHz, DMSO-d₆) δ 1.44–1.73 (8H,m), 1.93–2.06 (2H, q), 5.00 (2H, s), 6.88 (1H, d, J=8.1 Hz), 7.24–7.38(6H, m), 7.44–7.56 (5H, m), 9.64 (1H, s); MS (ESI(+ve)) m/z 399 (M−H)⁻.

Procedure B

A solution of5′-(2-Fluorophenyl)-spiro[cyclohexane-1,3′-[3H]indol-2′(1H)-one2(O-benzyloxime) (0.55 g, 1.37 mmol) in ethanol (15 mL) was added toPalladium on carbon (10%, 0.11 g) in ethanol (10 mL). The mixture wasstirred under an atmosphere of hydrogen (balloon) for 24 h at roomtemperature. The reaction mixture was filtered through a Celite plug andthe filtrate was concentrated in vacuo. The product was purified byflash silica gel chromatography (hexane:ethyl acetate, gradientelutions) to give the title compound (0.45 g, 1.12 mmol, 82%), mp.200–203° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 1.45–1.73 (8H, m) 1.96–2.00(2H, q) 6.83 (1H, d, J=7.9 Hz), 7.23–7.50 (6H, m), 9.42 (1H, s), 9.58(1H, s); MS (ESI(+ve)) m/z 311 (M+H)⁺.

EXAMPLE 475′-(4-FLUOROPHENYL)SPIRO[CYCLOHEXANE-1,3′-[3H]INDOL]-2′(1′H)-ONE OXIME

5′-(4-Fluorophenyl)-spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one2′(O-benzyloxime). Prepared from5′-bromospiro{cyclohexane-1,3′-[3H]indol}-2′(1′H)-one 2′(O-benzyloxime)(1.0 g, 2.6 mmol), and 4-fluorophenyl boronic acid (0.72 g, 5.2 mmol)according to Example 45 procedure A. The product was purified by flashsilica gel chromatography; (eluant: 10:0.5 hexane:ethyl acetate) to givethe desired product (0.70 g, 1.7 mmol, 67%) as a viscous oil. ¹H NMR(500 MHz, DMSO-d₆) δ 1.42–1.77 (8H, m), 1.95–1.99 (2H, q), 5.00 (2H, s),6.84 (1H, d, J=8.1 Hz), 7.21–7.63 (1H, m), 9.58 (1H, s); MS (ESI(−ve))m/z 399 (M−H)⁻.

The product was synthesized using5′-(4-Fluorophenyl)-spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one2′-(O-benzyloxime) (0.70 g, 1.74 mmol), according to Example 45procedure B. The product was purified by flash silica gelchromatography; (hexane:ethyl acetate, gradient elution) to give thetitle compound (0.44 g, 1.4 mmol, 81%), Mp. 205–208° C.; ¹H NMR (500MHz, DMSO-d₆) δ 1.43–1.77 (8H, m), 2.00–2.05 (2H, q), 6.80 (1H, d, J=8.2Hz), 7.21–7.24 (2H, m), 7.33–7.35 (1H, dd, J=1.9 Hz), 7.49 (1H, s),7.60–7.63 (2H, m), 9.35 (1H, s), 9.56 (1H, s); MS (ESI(+ve)) m/z 311(M+H)⁺.

EXAMPLE 485′-(3,4-DIFLUOROPHENYL)SPIRO[CYCLOHEXANE-1,3′-[3H]INDOL]-2′(1′H)-ONEOXIME

5′-(3,4-Difluorophenyl)-spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one2′(O-benzyloxime). Prepared from5′-bromospiro{cyclohexane-1,3′-[3H]indol}-2′(1′H)-one 2′(O-benzyloxime)(1.0 g, 2.6 mmol) and 3,4-diflurophenyl boronic acid (1.6 g, 5.2 mmol ofa 50% solution of acid in THF/water) according to Example 45 procedureA. The product was purified by flash silica gel chromatography (eluant:10:0.5 hexane:ethyl acetate) to give the desired product (0.75 g, 1.7mmol, 69%) as a viscous oil. ¹H NMR (500 MHz, DMSO-d₆) δ 1.41–1.78 (8H,m), 1.95–1.99 (2H, q), 5.00 (2H, s), 6.82 (1H, d), 7.28–7.46 (8H, m),7.58 (1H, q), 7.67–7.71 (1H, m), 9.61 (1H, s); MS (ESI(−ve)) m/z 417(M−H)⁻.

Reaction of the last cited compound (0.70 g, 1.6 mmol) according toExample 45 procedure B, afforded the title compound (0.44 g, 1.3 mmol,80%), ¹H NMR (500 MHz, DMSO-d₆) δ 1.42–1.79 (8H, m), 2.01–2.05 (2H, q),6.78–6.80 (1H, d), 7.39–7.46 (3H, m), 7.55 (1H, s), 7.70 (1H, m), 9.10(1H, s), 9.59 (1H, s); MS (ESI(+ve)) m/z 329 (M+H)⁺.

EXAMPLE 495′-(3-METHOXYPHENYL)SPIRO[CYCLOHEXANE-1,3′-[3H]INDOL]-2′(1′H)-ONE OXIME

5′-(3-Methoxyphenyl)-spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one2′-(O-benzyloxime). Prepared from5′-bromospiro{cyclohexane-1,3′-[3H]indol}-2′(1′H)-one 2′(O-benzyloxime)(1.0 g, 2.6 mmol) and 3-methoxyphenyl boronic acid (0.79 g, 5.2 mmol)according to Example 45 procedure A. The product was purified by flashsilica gel chromatography; (eluant: 10:0.5 hexane:ethyl acetate) to givethe desired product (0.80 g, 1.9 mmol, 75%) as a viscous oil. ¹H NMR(500 MHz, DMSO-d₆) δ 1.43–1.78 (8H, m), 1.95–2.00 (2H, q), 3.80 (3H, s),5.00 (2H, s), 6.82–6.86 (2H, m), 7.10–7.16 (2H, m), 7.28–7.53 (10H, m),9.57 (1H, s); MS (ESI(−ve)) m/z 411 (M−H)⁻.

Reaction of the last cited compound (0.80 g, 1.9 mmol) according toExample 45 procedure B, afforded the title compound (0.48 g, 1.4 mmol,77%), as a white solid. Mp. 101–104° C.; ¹H NMR (500 MHz, DMSO-d₆) δ1.44–1.78 (8H, m), 1.99–2.03 (2H, q), 3.81 (3H, s), 6.78 (1H, d), 6.85(1H, d), 7.10–7.16 (2H, m), 7.30–7.38 (2H, m), 7.50 (1H, d), 9.35 (1H,s), 9.56 (1H, s); MS (ESI(+ve)) m/z 323 (M+H)⁺.

EXAMPLE 505′-(3-NITROPHENYL)SPIRO[CYCLOHEXANE-1,3′-[3H]INDOL]-2′(1′H)-ONE OXIME

5′-(3-Nitrophenyl)-spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one2′(O-benzyloxime). Prepared from5′-bromospiro{cyclohexane-1,3′-[3H]indol}-2′(1′H)-one 2′(O-benzyloxime)(1.0 g, 2.6 mmol) and 3-Nitrophenyl boronic acid (0.86 g, 5.2 mmol)according to Example 45 procedure A. Purification by flash silica gelchromatography (eluant: 10:0.5 hexane:ethyl acetate) afforded thedesired compound (0.60 g, 1.4 mmol, 55%) as a viscous oil. ¹H NMR (500MHz, DMSO-d₆) δ 1.42–1.82 (8H, m), 2.02–2.04 (2H, q), 5.01 (2H, s), 6.88(1H, d), 7.28–7.71 (8H, m), 8.08–8.13 (2H, m), 8.38 (1H, d), 9.69 (1H,s); MS (ESI(−ve)) m/z 426 (M−H)⁻.

Procedure C

The last cited compound (0.54 g, 1.26 mmol) was dissolved in drymethylene chloride (25 mL) and cooled to −78° C. under nitrogen. Borontribromide (3.8 mL, 3.8 mmol, 1.0 M in methylene chloride) was addeddrop-wise over 5 minutes. After 30 minutes the reaction was quenchedwith saturated sodium bicarbonate (5 mL). The reaction mixture wasallowed to warm to room temperature, the layers were separated and theaqueous layer was extracted with methylene chloride. The combinedorganic layers were dried (Na₂SO₄), filtered, and the solvent removed invacuo. The product was purified by flash silica gel chromatography(eluant: 8:1 hexane:ethyl acetate) to give afford the title compound(0.33 g, 0.9 mmol, 78%). Mp. 221–224° C.; ¹H NMR (500 MHz, DMSO-d₆) δ1.42–1.83 (8H, m), 1.99–2.07 (2H, q), 6.84–6.85 (1H, dd), 7.50–7.52 (1H,m), 7.67–7.71 (2H, m), 8.08–8.12 (2H, m), 8.37–8.38 (1H, d), 9.48 (1H,s), 9.64 (1H, s); MS (ESI(+ve)) m/z 338 (M+H)⁺.

EXAMPLE 515′-(3-CYANOPHENYL)SPIRO[CYCLOHEXANE-1,3′-[3H]INDOL]-2′(1′H)-ONE OXIME

3-[Spiro[cyclohexane-1,3′-[3H]indol]-(1′H)-one-2′-(O-benzyloxime)]benzonitrile[3H]indol]-5-yl]benzonitrile.Prepared from 5′-bromospiro{cyclohexane-1,3′-[3H]indol}-2′(1′H)-one2′(O-benzyloxime) (1.0 g, 2.6 mmol) and 3-cyanophenyl boronic acid (0.76g, 5.2 mmol) according to Example 45 procedure A. The product waspurified by flash silica gel chromatography (eluant: 10:0.5 hexane:ethylacetate) to give the desired product (0.75 g, 1.8 mmol, 71%) as aviscous oil. ¹H NMR (500 MHz, DMSO-d₆) δ 1.41–1.81 (8H, m), 1.96–2.03(2H, q), 5.01 (2H, s), 6.86 (1H, d), 7.28–7.33 (9H, m), 7.95–7.97 (1H,d), 8.12 (1H, s), 9.65 (1H, s); MS (ESI(−ve)) m/z 406 (M−H)⁻.

Reaction of the last cited compound (0.17 g, 0.43 mmol) and borontribromide (1.2 mL, 1.2 mmol) according to Example 49 procedure Cafforded the title compound (0.06 g, 0.2 mmol, 47%) as a white solid,Mp. 198–200° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 1.41–1.80 (8H, m),1.97–2.04 (2H, q), 6.80 (1H, q), 7.45–7.69 (4H, m), 7.93–7.95 (1H, dd),8.10 (1H, s), 9.42 (1H, s), 9.59 (1H, s); (ESI(+ve)) m/z 318 (M+H)⁺.

EXAMPLE 523-[1′,2′-DIHYDRO-2′-(HYDROXYIMINO)SPIRO[CYCLOHEXANE-1,3′-[3H]INDOL]-5′YL]-5-FLUOROBENZONITRILE

To a solution of 3-fluoro-5-cyano-bromobenzene (0.4 g, 2.0 mmol) in dryDMF (10 ml) was added diboron pinacolate ester (0.63 g, 2.5 mmol),potassium acetate (0.65 g, 6.7 mmol) and PdCl₂ (dppf) (0.2 g) and thereaction was heated to 80° C. under a nitrogen atmosphere. After 8 h.from 5′-bromospiro{cyclohexane-1,3′-[3H]indol}-2′(1′H)-one2′(O-benzyloxime) (0.2 g, 0.5 mmol), PdCl₂ (dppf) (0.05 g) and sodiumcarbonate (1.30 g, 12.5 mmol) were added and heating at 80° C. wascontinued. After 8 h., the reaction was cooled and partitioned betweenwater and ethyl acetate, the organic layer was washed with brine, dried(MgSO₄) and evaporated. The residue was purified by columnchromatography (SiO₂, EtOAc:hexane 1:20) to give the desired product(0.14 g, 0.33 mmol, 66%).

Reaction of the last cited compound (0.14 g, 0.33 mmol) and borontribromide (1.0 ml, 1.0 mmol) according to Example 49 procedure Cafforded the title compound (0.019 g, 0.05 mmol, 17%): ¹H NMR (300 MHz,DMSO-d₆) δ 9.65 (s, 1H), 9.49 (s, 1H), 8.04 (m, 1H), 7.89 (dt, 1H,J=10.5 and 2 Hz), 7.72–7.68 (m, 2H), 7.54 (d, 1H, J=8.1 Hz), 6.80 (d,1H, J=8.1 Hz), 2.05–1.99 (m, 2H), 1.84–1.76 (m, 2H) and 1.65–1.44 (m,6H): MS (ESI(+ve)) m/z 336 (M+H)⁺.

EXAMPLE 535-(SPIRO[CYCLOHEXANE-1,3′-[3H]INDOL]-2′-(HYDROXYIMINO)-5′-YL)-4-METHYL-2-THIOPHENECARBONITRILE

4-Methyl-5-trimethylstannanyl-thiophene-2-carbonitrile. Prepared from5-bromo-4-methyl-thiophene-2-carbonitrile (3.08 g, 15.2 mmol),tetrakistriphenyl phosphine Pd (0) (0.82 g, 0.71 mmol), hexamethylditin(5.0 g, 15.2 mmol) and ethylene glycol dimethyl ether (20 mL) undernitrogen. The mixture was heated to reflux for 14 hours. The reactionmixture was concentrated in vacuo and purified using flash silica gelchromatography (eluant: 2% MeOH: methylene chloride) to recover thedesired product (2.8 g, 0.01 mmol, 67%) as a runny oil. ¹H NMR (300 MHz,DMSO-d₆) δ 0.41 (9H, s), 2.28 (3H, s), and 7.83 (1H, s).

The last cited compound (0.20 g, 0.50 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.02 g, 0.03 mmol) andtriphenylarsine (0.03 g, 0.13 mmol) in DME (8.0 mL) were stirred undernitrogen for 20 minutes.5′-Bromospiro{cyclohexane-1,3′-[3H]indol}-2′(1′H)-one 2′-(O-benzyloxime)(0.18 g, 0.64 mmol) was added in a solution of DME (2.0 mL). Thesolution was heated to reflux overnight. The reaction solution wasconcentrated in vacuo and purified by flash silica gel chromatography(eluant 12:1 hexane:ethyl acetate) to give the crude product (0.10 g,0.25 mmol, 50%) which was used without further purification

Boron tribromide (2.6 mL, 2.6 mmol of a 1.0 M solution in methylenechloride) was added to a solution of the last product (0.37 g, 0.86mmol) in dry methylene chloride (1.7 mL) at −78° C. The solution wasstirred for 30 minutes and quenched with saturated sodium bicarbonate(10 mL). The mixture was allowed to warm to room temperature and thelayers were separated. The organic layer was dried (Na₂SO₄), filteredand concentrated in vacuo to give crude product which was purified byflash silica gel chromatography (eluant: 6:1 hexane:ethyl acetate) togive the title compound (0.02 g, 24%): Mp. 173–176° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 1.44–1.73 (8H, m), 1.96–2.00 (2H, m), 2.28 (3H, s), 6.82–6.84(1H, m), 7.24–7.26 (1H, dd, J=1.7 Hz), 7.38 (1H, m), 7.82 (1H, m), 9.51(1H, m), 9.66 (1H, m); MS (ESI(+ve)) m/z 338 (M+H)⁺.

EXAMPLE 545-(SPIRO[CYCLOHEXANE-1,3′-[3H]INDOL]-2′(HYDROXYIMINO)-5′-YL)-2-THIOPHENECARBONITRILE

To a solution of 2-cyanothiophene (1.0 g, 9.16 mmol) andtri-iso-propylborate (2.3 ml, 10 mmol) in dry THF (30 ml) under nitrogenat −78° C. was added, dropwise, lithium hexamethyldisilazide (1M in THF,10 ml, 10 mmol). After 30 min., the reaction was quenched with 1N HCl,then extracted with ethyl acetate, the organic layer was washed withwater, dried (Na₂SO₄) and evaporated to the product (1.25 g, 8.17 mmol,89%) which was used without further purification: ¹H NMR (500 MHz,DMSO-d₆) δ 8.75 (br s, 2H), 7.97 (d, 1H, J=8 Hz) and 7.73 (d, 1H, J=8Hz): MS (ESI(−ve)) m/z 152 (M−H)⁻.

Prepared from the last cited product (0.91 g, 5.95 mmol) and5′-bromospiro{cyclohexane-1,3′-[3H]indol}-2′(1′H)-one 2′(O-benzyloxime)(1.53 g, 3.97 mmol) according to Example 45 procedure A. Purification byflash silica gel chromatography (eluant: 5:1 hexane:THF) gave thedesired product (0.66 g, 1.59 mmol) which was used without furtherpurification: MS (ESI(−ve)) m/z 412 (M−H)⁻.

Reaction of the last cited compound (0.60 g, 1.45 mmol) and borontribromide (1M in dichloromethane, 5 mL, 5 mmol) according to Example 49procedure C afforded the title compound (0.036 g, 0.11 mmol, 8%): ¹H NMR(300 MHz, DMSO-d₆) δ 9.71 (s, 1H), 9.62 (s, 1H), 7.92 (d, 1H, J=3.9 Hz),7.63 (d, 1H, J=1.5 Hz), 7.54 (d, 1H, J=3.9 Hz), 7.47 (dd, 1H, J=8.1 and1.6 Hz), 6.78 (d, 1H, J=8.1 Hz), 2.13–1.90 (m, 2H) and 1.78–1.60 (m,6H): MS (ESI(+ve)) m/z 324 (M+H)⁺.

EXAMPLE 554-(SPIRO[CYCLOHEXANE-1,3′-[3H]INDOL]-2′(HYDROXYIMINO)-5′-YL)-2-THIOPHENECARBONITRILE

4-(Trimethylstannyl)-2-thiophenecarbonitrile. A solution of3-bromo-2-thiophenecarbonitrile (0.8 g, 4.3 mmol),tetrakis(triphenylphosphine)palladium(0) (0.25 g, 0.2 mmol) andhexamethylditin (1.4 g, 4.3 mmol) in dimethoxyethane (5 cm³) was heatedunder reflux for 14 h then cooled to RT. The reaction mixture wasabsorbed onto florisil and purified by column chromatography (SiO₂,methylene chloride:hexane 1:9) to afford the subtitled compound (1.04 g,3.8 mmol, 90%) as a clear viscous oil: ¹H NMR (CDCl₃) δ 0.35 (s, 9H),7.56 (d, J=0.9 Hz, 1H), 7.66 (d, J=0.9 Hz, 1H).

To a solution of 5′-bromospiro{cyclohexane-1,3′-[3H]indol}-2′(1′H)-one2′(O-benzyloxime) (1.65 g, 4.28 mmol),4-(trimethylstannyl)-2-thiophenecarbonitrile (1.48 g, 5.44 mmol),triphenylarsine (330 mg) in dry dimethoxy ethane (20 ml), under anitrogen atmosphere was added bis(triphenylphosphine)palladium (II)chloride, and the mixture was heated under reflux for 16 h. Aftercooling to room temperature the mixture was evaporated, and the residuepurified by column chromatography (SiO₂, EtOAc:hexane, gradient elution)to afford the desired product (0.61 g, 1.47 mmol, 56%).

Reaction of the last cited compound (0.61 g, 1.47 mmol) and borontribromide (1M in dichloromethane, 4.5 mL, 4.5 mmol) according toExample 49 procedure C afforded the title compound (0.084 g, 0.26 mmol,18%): ¹H NMR (300 MHz, DMSO-d₆) δ 9.61 (s, 1H), 9.42 (s, 1H), 8.41 (s,1H), 8.18 (s, 1H), 7.65 (s, 1H), 7.48 (dd, 1H, J=8.1 and 0.9 Hz), 6.76(d, 1H, J=8.1 Hz), 2.03–1.96 (m, 2H) and 1.78–1.42 (m, 6H): MS(ESI(+ve)) m/z 324 (M+H)⁺.

EXAMPLE 565-(SPIRO[CYCLOHEXANE-1,3′-[3H]INDOL]-2′-(HYDROXYIMINO)-5′-YL)-1H-PYRROLE-1-METHYL-2-CARBONITRILE

2-{5′[spiro[cyclohexane-1,3′-[3H]indol]-(1′H)-one-2′(O-benzyloxime)]}-1H-pyrrole-1-carboxylicacid, tert-butyl ester. A solution of5′-bromospiro{cyclohexane-1,3′-[3H]indol}-2′(1′H)-one 2′(O-benzyloxime)(7.4 g, 19.17 mmol) and tetrakis (triphenylphosphine)palladium (0) (2.5g, 2.00 mmol) in DME (100 ml) was stirred under nitrogen for 15 minutes.To the solution was added 1-tert-butoxycarbonylpyrrole boronic acid (5.5g, 26 mmol) and 1M sodium carbonate (50 ml). The mixture was heated to80° C. for 6 hours and allowed to cool. The reaction mixture was pouredinto water and extracted with ethyl acetate (3×100 ml). The organiclayers were combined and dried over magnesium sulfate. The solution wasfiltered, concentrated in vacuo, and the residue was purified by flashchromatography on silica gel (4.5:1 Hexane/ethylacetate) to give theproduct (7.7 g, 88%) as a white solid. ¹H NMR (DMSO-d₆, 300 MHz) δ 1.28(s, 9H), 1.55–1.66 (m, 8H), 1.83–1.98 (m, 2H), 4.99 (s, 2H), 6.12–6.14(m, 1H), 6.22 (t, 1H, J=3.26 Hz), 6.76 (d, 1H, J=7.9 Hz), 7.02 (dd, 1H,J=7.98, 1.4 Hz), 7.19 (s, 1H) 7.27–7.31 (m, 2H), 7.35 (t, 1H, J=6.8 Hz),7.43 (d, 1H, J=8 Hz), 9.55 (s, 1H).

5′-(1-tert-Butoxycarbonyl-1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′-(1′H)one-2′-(O-benzyloxime)-1′-carboxylicacid, tert-butyl ester. To a solution of2-{5′[spiro[cyclohexane-1,3′-[3H]indol]-(1′H)-one-2′-(O-benzyloxime)]}-1H-pyrrole-1-carboxylicacid, tert-butyl ester (7.7 g, 16.38 mmol) in THF (anhydrous, 100 mL)was added sodium hydride (0.665 g, 17 mmol) after hydrogen evolutionceased di-tert-butyldicarbonate (10.9 g, 50 mmol) and DMAP (0.20 g) wasadded and the reaction stirred at 65° C. for 18 hours. The reactionmixture was poured into water and extracted with ethyl acetate. Theorganic layers were combined, and dried over magnesium sulfate. Thesolution was filtered, concentrated in vacuo, to give the product (9.0g, 15.76 mmol) which was taken directly to the next step.

To a solution of5′-(1-tert-Butoxycarbonyl-1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′-(1′H)one-2′-(O-benzyloxime)-1′-carboxylicacid, tert-butyl ester (9.0 g, 15.76 mmol) in THF (anhydrous, 75 mL) at−78° C. was added chlorosulfonyl isocyanate (1.55 mL, 17.54 mmol). After90 minutes, DMF (21 mL, 275 mmol) was added and the reaction was allowedto warm to room temperature. The reaction was poured into water (200 mL)and extracted with ethyl acetate (2×100 mL). The organic layers combinedand dried over magnesium sulfate, filtered and concentrated in vacuo.Purification by flash column chromatography on silica gel (10% ethylacetate/Hexane) gave5′-(5-cyano-1-tert-butoxycarbonyl-1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)one-2′(O-benzyloxime)-1′-carboxylicacid, tert-butyl ester (7.6 g, 82%) as a white powder. ¹H NMR (DMSO-d₆,300 MHz) δ 1.30 (s, 9H), 1.38 (s, 9H), 1.58–1.83 (m, 8H), 1.72–1.73 (m,2H), 5.0 (s, 2H), 6.44–6.45 (d, 1H, J=3.76 Hz), 7.25–1.46 (m, 10H).

5′-(5-Cyano-1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)one-2′-(O-benzyloxime)-1′-carboxylicacid, tert-butyl ester. To a solution of5′-(5-cyano-1-tert-butoxycarbonyl-1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)one-2′(O-benzyloxime)-1′-carboxylicacid, tert-butyl ester (7.6 g, 3.25 g, 48 mmol) in THF (anhydrous, 30mL) was added a solution of sodium ethoxide in ethanol (120 mL). Thereaction mixture was heated to 80° C. and stirred overnight. The mixturewas cooled to room temperature and concentrated in vacuo. The residuewas dissolved in ethyl acetate and washed with water, brine, and driedover magnesium sulfate. The solvent was evaporated in vacuo to affordthe product (6.1 g, 95%). ¹H NMR (DMSO, 500 MHz) δ 1.38 (s, 9H),1.63–1.74 (m, 8H), 1.88–1.97 (m, 2H), 5.08 (s, 2H) 6.69–6.7 (d, 1H,J=0.8 Hz), 6.98–6.99 (d, 1H, J=0.7 Hz), 7.29–7.37 (m, 1H), 7.35 (m, 2H),7.42 (m, 3H), 7.63 (dd, 1H, J=1.8, 0.3 Hz), 7.76 (d, 1H, J=0.4 Hz).

5′-(5-Cyano-1-methyl-1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′-(O-benzyloxime)-1′-carboxylicacid, tert-butyl ester. To5′-(5-cyano-1H-pyrrol-2-yl)spiro[cylohexane-1,3′-[3H]indol]-2′(1′H)one-2′-(O-benzyloxime)-1′-carboxylicacid, tert-butyl ester (6.1 g, 12.29 mmol) in DMF (75 mL) was addedpotassium carbonate (6.5 g, 47 mmol) and MeI (1 mL, 15.4 mmol) and thereaction mixture was stirred at room temperature for 2.5 hours. Thereaction mixture was poured into water and extracted with ethyl acetate.The organic layer was washed with brine and the solvent was concentratedin vacuo. To give the desired product (6.1 g, 12.29 mmol) which wascarried on to the next step without further purification. ¹H NMR (DMSO,300 MHz) δ 1.38 (s, 9H), 1.62–1.98 (m, 10H), 3.71 (s, 3H), 5.08 (s, 2H),6.34 (d, 1H, J=4.1 Hz), 7.03 (d, 1H, J=3.99 Hz), 7.30–7.53 (m, 8H).

5-{5′-Spiro[cyclohexane-1,3′-[3H]indol]-(1′H)-one-2′-(O-benzyloxime)}-1H-pyrrole-1-methyl-2-carbonitrile.5′-(5-Cyano-1-methyl-1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′-(O-benzyloxime)-1′-carboxylicacid, tert-butyl ester (6.1 g, 12.29 mmol) was dissolved in dioxane (5mL) and 4 M HCl in dioxane (10 mL) was added and the reaction heated to45° C. for 3.5 hours. The mixture was carefully neutralized with sodiumbicarbonate (sat.). The reaction mixture was poured into water andextracted with ethyl acetate. The organic layer was washed with brineand dried over magnesium sulfate. The solvent was evaporated in vacuo.Purification by column chromatography on silica gel (5% ethylacetate/hexane) gave the product (4.36 g, 94%). ¹H NMR (DMSO-d₆, 300MHz) δ 1.57–1.7 (m, 8H), 1.9–2.05 (m, 2H), 3.68 (s, 3H), 5.00 (s, 2H),6.25 (d, 1H, J=3.92 Hz), 6.85 (d, 1H, J=8.03 Hz), 7.00 (d, 1H, J=4.08Hz), 7.2–7.44 (m, 7H), 9.7 (s, 1H)

To5-{5′-spiro[cyclohexane-1,3′-[3H]indol]-(1′H)-one-2′-(O-benzyloxime)}-1H-pyrrole-1-methyl-2-carbonitrile(4.36 g, 10.6 mmol) in methylene chloride (50 mL) was added 1M borontribromide (35 mL, in methylene chloride) at −78° C. The reactionmixture was allowed to warn to room temperature. After 4 hours, thereaction mixture was quenched with saturated sodium bicarbonate (100mL). The organic layer was collected and the aqueous layer was extractedwith ethyl acetate (2×100 mL), organic layers combined, washed withbrine, dried over magnesium sulfate, and the solvent evaporated invacuo. The residue was purified by flashed chromatography on silica gel(7:3 hexane/ethylacetate) to give the title compound (1.35 g, 40%) as awhite solid. ¹H NMR (DMSO-d₆, 300 MHz) δ 1.58–1.71 (m, 8H), 1.99–2.00(m, 2H), 3.69 (s, 3H) 6.24 (d, 1H, J=4.07 Hz), 6.8 (d, 1H, J=8.05 Hz),6.99 (d, 1H, J=4.01 Hz), 7.20 (dd, 1H, J=8.04, 1.57 Hz), 7.36 (d, 1H,J=1.12 Hz), 9.48 (s, 1H), 9.62 (s, 1H).

EXAMPLE 575-(SPIRO[CYCLOHEXANE-1,3′-[3H]INDOL]-2′-(HYDROXYIMINO)-5′-YL)-1H-PYRROLE-2-CARBONITRILE

5-(spiro[cyclohexane-1,3′-[3]indole]-2′(1H)-(O-benzyloxime))-1H-pyrrole-2-carbonitrile.Prepared from5′-(5-Cyano-1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)one-2′-(O-benzyloxime)-1′-carboxylicacid, tert-butyl ester (0.395 g, 0.796 mmol) dissolved in 2 mL of THFand 4M HCl Dioxane/water (10 mL) following the procedure used to prepare5-{5′-spiro[cyclohexane-1,3′-[3H]indol]-(1′H)-one-2′-(O-benzyloxime)}-1H-pyrrole-1-methyl-2-carbonitrilethe desired product was obtained (0.220 g, 0.745 mmol, 95%). ¹H NMR(DMSO-d₆, 500 MHz) δ 1.44–1.50 (m, 1H), 1.61–1.70 (m, 7H), 1.94–1.99 (m,2H), 5.0 (s, 2H), 6.55 (d, 1H, J=4 Hz), 6.79 (d, 1H, J=8.0 Hz), 6.95 (d,1H, J=4 Hz), 7.27–7.31 (m, 1H), 7.34–7.37 (m, 2H), 7.42–7.43 (m, 2H),7.47 (dd, 1H, J=8.0, 1.4 Hz), 7.65 (d, 1H, J=1.5 Hz), 9.65 (s, 1H), 12.4(s, 1H).

The title compound was prepared from5-(spiro[cyclohexane-1,3′-[3]indole]-2′(1H)-(O-benyloxime))-1H-pyrrole-2-carbonitrile(0.325 g, 0.82 mmol) and 1M Boron tribromide (6 mL in methylenechloride), following the procedure for5-(spiro[cyclohexane-1,3′-[3H]indole]-2′-(hydroxyimino)-5′-yl)-1H-pyrrole-1-methyl-2-carbonitrile,to obtain the product as an off white solid (0.110 g, 0.326 mmol, 44%).¹H-NMR (DMSO-d₆, 500 MHz) δ 1.46–1.5 (m, 1H), 1.62–1.71 (m, 7H),1.95–2.05 (m, 2H), 6.55 (d, 1H, J=4.0 Hz), 6.75 (d, 1H, J=8.0 Hz), 6.94(d, 1H, J=3.47 Hz), 7.45 (dd, 1H, J=8.1, 1.73 Hz), 7.63 (d, 1H, J=1.73Hz), 9.42 (s, 1H), 9.59 (s, 1H), 12.39 (s, 1H).

EXAMPLE 584-(SPIRO[CYCLOHEXANE-1,3′-[3H]INDOLE]-2′(ACETOXYIMINO)-5′-YL)-2-THIOPHENECARBONITRILE

To a solution of4-(Spiro[cyclohexane-1,3′-[3H]indole]-2′(hydroxyimino)-5′-yl)-2-thiophenecarbonitrile(2.21 g, 6.83 mmol) and acetic anhydride (1 ml) indichloromethane-pyridine (30 ml, 9:1) was added 4-dimethylaminopyridine(250 mg) at room temperature. After 3 h., the mixture was diluted withdichloromethane, washed with water, dil. Hydrochloric acid, water, dried(MgSO₄), and evaporated. The residue was purified by columnchromatography (EtOAc:hexane, gradient elution) to afford the titlecompound (0.84 g, 2.29 mmol, 33%) as a white solid: MS (ESI (+ve)) m/z366 [M+H]⁺.

EXAMPLE 593-FLUORO-N′-HYDROXY-5-[2′-(HYDROXYAMINO)SPIRO[CYCLOHEXANE-1,3′-[3H]INDOL]-5′-YL]BENZENECARBOXIMIDAMIDE

5′-(3-Cyano-5-fluorophenyl)-2-(methylthio)spiro[cyclohexane-1,3′-[3H]indole].Prepared from3-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluorobenzonitrile(0.451 g, 1.34 mmol) according to the procedure described in Example 42to afford the desired product (0.316 g, 0.90 mmol, 67%): ¹H NMR (DMSO,300 MHz) δ 7.74 (d, 1H, J=1.7 Hz), 7.68 (t, 1H, J=1.4 Hz), 7.58 (d, 1H,J=8.0 Hz), 7.54 (t, 1H, J=2.3 Hz), 7.50 (dd, 1H, J=8.0 and 1.9 Hz),7.33–7.29 (m, 1H), 2.67 (s, 3H), 2.04–1.78 (m, 7H) and 1.58–1.50 (m,3H); MS (ESI(+ve)) m/z 351 (M+H)⁺.

To a solution of the last cited product (0.30 g, 0.88 mmol) in DMSO (10ml) was added hydroxylamine (50% aqueous solution, 1 ml), and thereaction was heated to 120° C. After 1 h., the mixture was cooled,partitioned between saturated aqueous ammonium chloride andethylacetate. The organic layer was washed with water, brine, dried(MgSO₄), and evaporated. The residue was purified by columnchromatography (SiO₂, 5% MeOH in dichloromethane) to afford the titlecompound (0.079 g, 0.23 mmol, 26%) as a white foam: ¹H NMR (DMSO, 300MHz) δ 9.79 (s, 1H), 9.61 (s, 1H), 9.42 (s, 1H), 7.73 (s, 1H), 7.61 (d,1H, J=1.3 Hz), 7.46 (dd, 1H, J=8.3 and 1.5 Hz), 7.34 (d, 1H, J=10 Hz),6.81 (d, 1H, J=8.0 Hz), 6.01 (s, 2H), 2.11–2.02 (m, 2H) and 1.81–1.56(m, 8H): MS (ESI(+ve)) m/z 369 (M+H)⁺.

EXAMPLE 60N′-HYDROXY-5-(SPIRO[CYCLOHEXANE-1,3′-[3H]INDOL]-2′(HYDROXYIMINO)-5′-YL)-4-METHYL-2-THIOPHENECARBOXIMIDAMIDE

4-Methyl-5-(spiro[cyclohexane-1,3′[3H]indol]2′-(methylthio)-5′-yl)-2-thiophenecarbonitrile.To potassium tert-butoxide (0.32 g, 2.6 mmol) in THF was added5-(1′,2′-Dihydro-2′-thioxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-4-methyl-2-thiophenecarbonitrile(0.84 g, 2.5 mmol). After 15 minutes, methyl iodide (0.50 g, 3.48 mmol)was added. After 3 hours, reaction was poured into ammonium chloride(sat.) and extracted with ethylacetate. The organic layers were combinedand dried over magnesium sulfate. The solution was filtered,concentrated in vacuo, and the residue was purified by flashchromatography on silica gel (4:1 Hexane/ethyl acetate) to give thedesired product (0.530 g, 85%). (DMSO, 300 MHz) δ 1.48 (m, 3H), 1.70 (m,2H), 1.81 (m, 5H), 2.32 (s, 3H), 2.62 (s, 3H), 7.48 (dd, 1H, J=7.87 Hz,1.46 Hz), 7.5 (d, 1H, J=8.05 Hz), 7.77 (d, 1H, J=1.46 Hz), 7.88 (s, 1H).

To4-methyl-5-(spiro[cyclohexane-1,3′[3H]indol]2′-(methylthio)-5′-yl)-2-thiophenecarbonitrile(0.450 g, 1.3 mmol) in DMSO (1 mL) was added hydroxylamine hydrochloride(2 mL, 50% sol. in water) and heated to 100° C. for 2.5 hours. Water wasadded until solution became slightly turbid, allowed the mixture to coolto room temperature. The white solid was filtered, collected anddissolved in ethyl acetate and dried over magnesium sulfate. Thesolution was filtered, concentrated in vacuo, giving (0.320 g, 69%).(DMSO-d₆, 500 MHz) δ 1.4–1.74 (m, 8H), 1.94–2.4 (m, 2H), 2.54 (s, 3H),5.8 (s, 1H), 6.79 (d, 1H, J=8.0 Hz), 7.16 (dd, 1H, J=8.12, 1.83 Hz),7.39 (m, 2H), 9.42 (s, 1H), 9.56 (s, 1H), 9.58 (s, 1H).

EXAMPLE 61N′-HYDROXY-4-(SPIRO[CYCLOHEXANE-1,3′-[3H]INDOL]-2′(HYDROXYIMINO)-5′-YL-2-THIOPHENECARBOXIMIDAMIDE

4-(Spiro[cyclohexane-1,3′-[3H]indol]-2′-(methylthio)-5′-yl]-2-thiophenecarbonitrile(0.077 g, 0.237 mmol) was reacted with 50% solution of hydroxylamine (1mL) following the procedure for Example 59 to afford the title compound(0.016 g, 0.044 mmol, 20%). MS (ESI, (+ve)) m/z 357 [M+H]⁺.

EXAMPLE 62N′-HYDROXY-5-(SPIRO[CYCLOHEXANE-1,3′-[3H]INDOL]-2′-(HYDROXYIMINO)-5′-YL)-2-THIOPHENECARBOXIMIDAMIDE

The title compound was prepared from5-(spiro[cyclohexane-1,3′-[3H]indol]2′-(methylthio)-5′-yl]-2-thiophenecarbonitrile(0.500 g, 1.5 mmol) and a 50% solution of hydroxylamine (2 mL, excess)following the procedure for Example 59, to afford the product (0.200 g,0.56 mmol, 56%). ¹H NMR (DMSO-d₆, 500 MHz) δ 1.45–1.75 (m, 8H),1.97–2.06 (m, 2H), 5.89 (s, 1H), 6.74 (d, 1H, J=8 Hz), 7.3 (d, 1H, J=3.9Hz), 7.34 (dd, 1H, J=8.06, 1.46 Hz), 7.4 (d, 1H, J=8.0 Hz), 7.5 (d, 1H,J=1.95 Hz), 9.44 (s, 1H), 9.58 (s, 1H), 9.6 (s, 1H).

EXAMPLE 635′-(3-CHLOROPHENYL)SPIRO[CYCLOHEXANE-1,3′-[3H]INDOL]-2′-CYANAMIDE

5′-(3-Chlorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′-amine. To aturbid solution of5′-(3-Chlorophenyl)-N-hydroxyspiro[cyclohexane-1,3-[3H]indol]-2-amine(0.500 g; 1.53 mmol) in 25 mL of ethanol was added hydrazine hydrate(0.600 mL; 12.24 mmol). The solution was warmed to 55° C., whereRaney-nickel (50% in water) was added to the reaction to keep a constantevolution of gas. After 45 minutes, the hot reaction mixture wasfiltered through a Celite plug and rinsed with a copious amount of hotmethanol. The filtrate was concentrated in vacuo to give 0.890 g of anopaque solid. The product was purified by flash silica gelchromatography; (eluant, 2% to 8% methanol-methylene chloride with 0.1%ammonium hydroxide) to afford 0.310 g (65%) of the desired product as awhite solid. Mp. 118–120° C. ¹H NMR δ (300 MHz, DMSO-d₆) 1.31–1.46 (m,2H), 1.70–1.93 (m, 8H), 7.0 (d, 1H), 7.1 (br, 2H, 2NH), 7.31–7.34 (dt,1H, J=8 Hz), 7.41–7.46 (t, 2H), 7.55–7.58 (d, 1H), 7.62 (s, 1H), 7.72(s, 1H); MS (ECI(+ve)) m/z 311 (M+H)⁺.

1-tert-butoxycarbonyl-5′-(3-chlorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′-amine.To a solution of5′-(3-chlorophenyl)spiro[cyclohexane-1,3-[3H]indol]-2′-amine (0.310 g;0.96 mmol) in dry methylene chloride at 0° C. was added Di-tert-butyldicarbonate (0.252 g; 1.15 mmol) and 4-dimethylaminopyridine (0.117 g;0.96 mmol). The solution was allowed to warm to room temperature andstir 24 h. The reaction solution was diluted with water (50 mL) and thelayers were separated. The organic layer was dried over Na₂SO₄, filteredand concentrated in vacuo to give 0.355 g of a yellow oil. The productwas purified by flash silica gel chromatography; (eluant, 1% to 3%methanol-methylene chloride) to afford the desired product (0.081 g,20%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 1.58 (m, 2H), 1.63(s, 9H, Boc), 1.77–1.79 (m, 8H), 7.42–7.48 (m, 2H), 7.64–7.68 (m, 3H),7.70–7.80 (m, 2H), 9.72 (s, 1H, NH). MS (ECI(+ve)) m/z 411 (M+H)⁺.

1′-tert-Butoxycarbonyl-5′-(3-chlorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′-amine(0.120 g; 0.29 mmol) in 2.0 mL of dry DMF was added to a solution of4-dimethylaminopyridine (0.089 g; 0.73 mmol) and cyanogen bromide (0.077g; 0.73 mmol) in 4.0 mL of dry DMF at 0° C. The yellow solution washeated to 40° C. for 16 h. Work-up included pouring the reactionsolution into 0.1 N NaHCO₃ (50 mL) and extracting with ethyl acetate(3×50 mL). The combined organic layers were dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo to give 0.091 g of a yellow residue.The product was purified by flash silica gel chromatography; (stepwisegradient of 5:1 to 3:1 hexane:ethyl acetate) to afford 0.031 g (32%) ofthe product as a bright yellow solid. Mp. 225° C. (dec.). ¹H NMR (500MHz, DMSO-d₆) δ 1.46–1.73 (m, 8H), 1.89–1.90 (m, 2H), 7.13–7.16 (d, 1H),7.38–7.41 (dt, 1H, J=8 Hz), 7.45–7.50 (m, 1H), 7.60–7.63 (dd, 2H, J=6.4Hz), 7.71 (s, 1H), 7.85 (s, 1H), 12.1 (s, 1H, NH); MS (ECI(−ve)) m/z 336(M−H)⁻.

Other desirable compounds, which can be made according to the methodsdescribed herein, include5′-(3-Cyano-5-fluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′-ylidenecyanamide,5′-(5-Cyano-1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2-ylidenecyanamide,5′-(5-Cyano-1-methyl-1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′-ylidenecyanamide,5′-(5-Cyanothien-2-yl)spiro[cyclohexane-1,3′-[3H]indole]-2′-ylidenecyanamide,5′-(5-Cyano-3-methylthien-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′-ylidenecyanamide,5′-(5-Cyanothien-3-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′-ylidenecyanamide,3-(spiro[cyclohexane-1,3′-[3H]indole]-2′-(cyanomethylene)-5′-yl)-5-fluorobenzonitrile,5-(spiro[cyclohexane-1,3′-[3H]indole]-2′-(Cyanomethylene)-5′-yl)-1-methyl-1H-pyrrole-2-carbonitrile,5-(spiro[cyclohexane-1,3′-[3H]indole]-2′-(Cyanomethylene)-5′-yl)-thiophene-2-carbonitrile,5-(spiro[cyclohexane-1,3′-[3H]indole]-2′-(Cyanomethylene)-5′-yl)-4-methyl-thiophene-2-carbonitrile,and4-(spiro[cyclohexane-1,3′-[3H]indole]-2′-(Cyanomethylene)-5′-yl)-thiophene-2-carbonitrile.

All publications cited in this specification are incorporated herein byreference herein. While the invention has been described with referenceto a particularly preferred embodiment, it will be appreciated thatmodifications can be made without departing from the spirit of theinvention. Such modifications are intended to fall within the scope ofthe appended claims.

1. A compound of formula 1:

wherein: R₁ and R₂ are independently selected from the group consistingof H, alkyl, substituted alkyl, OH, O(alkyl), O(substituted alkyl), OAc,aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl,alkylheteroaryl), 1-propynyl, and 3-propynyl: R₃ is selected from thegroup consisting of H; R₄ is selected from the group consisting of H,halogen, CN, NH₂, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₁ to C₆alkoxy, substituted C₁ to C₆ alkoxy, C₁ to C₆ aminoalkyl, andsubstituted C₁ to C₆ aminoalkyl; R₅ is a substituted benzene ringcontaining the substituents X, Y and Z as shown below:

X is selected from the group consisting of H, halogen, OH, CN, C₁ to C₃alkyl, substituted C₁ to C₃ alkyl, C₁ to C₃ alkoxy, substituted C₁ to C₃alkoxy, C₁ to C₃ thioalkyl, substituted C₁ to C₃ thioalkyl, S(O)alkyl,S(O)₂alkyl, C₁ to C₃ aminoalkyl, substituted C₁ to C₃ aminoalkyl, NO₂,C₁ to C₃ perfluoroalkyl, 5 or 6 membered heterocyclic ring containing inits backbone 1 to 3 heteroatoms, CONH₂, CSNH₂, CONHalkyl, CSNHalkyl,CON(alkyl)₂, CSN(alkyl)₂, COR^(B), OCOR^(B), and NR^(C)COR^(B); R^(B) isselected from the group consisting of H, C₁ to C₃ alkyl, substituted C₁to C₃ alkyl, aryl, substituted aryl, C₁ to C₃ alkoxy, substituted C₁ toC₃ alkoxy, C₁ to C₃ aminoalkyl, and substituted C₁ to C₃ aminoalkyl;R^(C) is H, C₁ to C₃ alkyl, or substituted C₁ to C₃ alkyl; Y and Z areindependently selected from the group consisting of H, halogen, CN, NO₂,C₁ to C₃ alkoxy, C₁ to C₃ alkyl, and C₁ to C₃ thioalkyl; Q¹ is CR₈R₉; R₈and R₉ are independent substituents selected from the group consistingof H, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₃ to C₈ cycloalkyl,substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocyclic,substituted heterocyclic, NO₂, CN, and CO₂R₁₀; R₁₀ is C₁ to C₃ alkyl; orCR₈R₉ form a six membered ring as shown by the structure below:

or a pharmaceutically acceptable salt thereof.
 2. The compound accordingto claim 1, wherein: R₅ is the benzene ring of the formula:

X is selected from the group consisting of halogen, CN, CONH₂, CSNH₂,CONHalkyl, CSNHalkyl, CON(alkyl)₂, CSN(alkyl)₂, C₁ to C₃ alkoxy, C₁ toC₃ alkyl, NO₂, C₁ to C₃ perfluoroalkyl, 5 membered heterocyclic ringcontaining in its backbone 1 to 3 heteroatoms, and C₁ to C₃ thioalkoxy;Y is on the 4′ or 5′ position and is selected from the group consistingof H, halogen, CN, NO₂, C₁ to C₃ alkoxy, C₁ to C₄ alkyl, and C₁ to C₃thioalkyl.
 3. A pharmaceutical composition comprising a compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier or excipient.
 4. A compound offormula
 1.

wherein: R₁ and R₂ are independently selected from the group consistingof alkyl and substituted alkyl; R₃ is H; R₄ is selected from the groupconsisting of H, halogen, CN, NH₂, C₁ to C₆ alkyl, substituted C₁ to C₆alkyl, C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, C_(1 to C) ₆aminoalkyl, and substituted C₁ to C₆ aminoalkyl; R₅ is a substitutedbenzene ring containing the substituents X, Y and Z as shown below:

X is selected from the group consisting of H, halogen, OH, CN, C₁ to C₃alkyl, substituted C₁ to C₃ alkyl, C₁ to C₃ alkoxy, substituted C₁ to C₃alkoxy, C₁ to C₃ thioalkyl, substituted C₁ to C₃ thioalkyl, S(O)alkyl,S(O)₂alkyl, C₁ to C₃ aminoalkyl, substituted C₁ to C₃ aminoalkyl, NO₂,C₁ to C₃ perfluoroalkyl, 5 or 6 membered heterocyclic ring containing inits backbone to 3 heteroatoms, CONH₂, CSNH₂, CONHalkyl, CSNHalkyl,CON(alkyl)₂, CSN(alkyl)₂, COR^(B), OCOR^(B), and NR^(C)COR^(B); R^(B) isselected from the group consisting of H, C₁ to C₃ alkyl, substituted C₁to C₃ alkyl, aryl, substituted aryl, C₁ to C₃ alkoxy, substituted C₁ toC₃ alkoxy, C₁ to C₃ aminoalkyl, and substituted C₁ to C₃ aminoalkyl;R^(C) is H, C₁ to C₃ alkyl, or substituted C₁ to C₃ alkyl; Y and Z areindependently selected from the group consisting of H, halogen, CN, NO₂,C₁ to C₃ alkoxy, C₁ to C₃ alkyl, and C₁ to C₃ thioalkyl; Q¹ is CR₈R₉; R₈is H; R₉ is CN; or a pharmaceutically acceptable salt thereof.
 5. Acompound of formula 1:

wherein: R₁ and R₂ are alkyl; R₃ is H; R₄ is H; R₅ is a substitutedbenzene ring containing the substituents X, Y and Z as shown below:

X is selected from the group consisting of H, halogen, OH, CN, C₁ to C₃alkyl, substituted C₁ to C₃ alkyl, C₁ to C₃ alkoxy, substituted C₁ to C₃alkoxy, C₁ to C₃ thioalkyl, substituted C₁ to C₃ thioalkyl, S(O)alkyl,S(O)₂alkyl, C₁ to C₃ aminoalkyl, substituted C₁ to C₃ aminoalkyl, NO₂,C₁ to C₃ perfluoroalkyl, 5 or 6 membered heterocyclic ring containing inits backbone to 3 heteroatoms, CONH₂, CSNH₂, CONHalkyl, CSNHalkyl,CON(alkyl)₂, CSN(alkyl)₂, COR^(B), OCOR^(B), and NR^(C)COR^(B); R^(B) isselected from the group consisting of H, C₁ to C₃ alkyl, substituted C₁to C₃ alkyl, aryl, substituted aryl, C₁ to C₃ alkoxy, substituted C₁ toC₃ alkoxy, C₁ to C₃ aminoalkyl, and substituted C₁ to C₃ aminoalkyl;R^(C) is H, C₁ to C₃ alkyl, or substituted C₁ to C₃ alkyl; Y and Z areindependently selected from the group consisting of H, CN, NO₂, C₁ to C₃alkoxy, C₁ to C₃ alkyl, and C₁ to C₃ thioalkyl; Q¹ is CR₈R₉; R₈ and R₉are independent substituents selected from the group consisting of H, C₁to C₆ alkyl, substituted C₁ to C₆ alkyl, C₃ to C₈ cycloalkyl,substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocyclic,substituted heterocyclic, NO₂, CN, and CO₂R₁₀; R₁₀ is C₁ to C₃ alkyl; ora pharmaceutically acceptable salt thereof.